axonal transport and alzheimer's disease ...lafer/2008/stokin-goldstein06.pdfjor motor protein...

ANRV277-BI75-23 ARI 3 May 2006 10:43

Axonal Transport andAlzheimer’s DiseaseGorazd B. Stokin1 and Lawrence S.B. Goldstein2

1Institute of Clinical Neurophysiology, Division of Neurology, University MedicalCenter, SI-1525 Ljubljana, Slovenia; email: [email protected] Hughes Medical Institute, Department of Cellular and Molecular Medicine,School of Medicine, University of California San Diego, La Jolla, California92093-0683; email: [email protected]

Annu. Rev. Biochem.2006. 75:607–27

First published online as aReview in Advance onMarch 16, 2006

The Annual Review ofBiochemistry is online atbiochem.annualreviews.org

doi: 10.1146/annurev.biochem.75.103004.142637

Copyright c© 2006 byAnnual Reviews. All rightsreserved

0066-4154/06/0707-0607$20.00

Key Words

motor proteins, axons, axonal pathology, aging, neurodegeneration

AbstractIn contrast to most eukaryotic cells, neurons possess long, highlybranched processes called axons and dendrites. In large mammals,such as humans, some axons reach lengths of over 1 m. These lengthspose a major challenge to the movement of proteins, vesicles, and or-ganelles between presynaptic sites and cell bodies. To overcome thischallenge axons and dendrites rely upon specialized transport ma-chinery consisting of cytoskeletal motor proteins generating directedmovements along cytoskeletal tracks. Not only are these transportsystems crucial to maintain neuronal viability and differentiation,but considerable experimental evidence suggests that failure of ax-onal transport may play a role in the development or progression ofneurological diseases such as Alzheimer’s disease.

607

Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

Contents

INTRODUCTION. . . . . . . . . . . . . . . . . 608AXONAL TRANSPORT . . . . . . . . . . . 608

Overview of Axonal Transport . . . . 608Proteins Required for Axonal

Transport . . . . . . . . . . . . . . . . . . . . . 609Mechanisms of Axonal Transport . . 610Regulation of Axonal Transport . . . 611

AXONAL TRANSPORT, AGING,AND DISEASE . . . . . . . . . . . . . . . . . . 612Axonal Transport and Aging . . . . . . 612Impairments in Axonal Transport

and the Pathogenesis ofNeurodegenerative Diseases . . . 613

Impaired Axonal Transportas a Result of Diseases . . . . . . . . . 614

AXONAL TRANSPORT ANDALZHEIMER’S DISEASE . . . . . . . 614Overview of Alzheimer’s Disease . . 615Axonal Transport of Proteins

Linked to the Pathogenesis ofAlzheimer’s Disease. . . . . . . . . . . . 617

Axonal Functions of ProteinsLinked to the Pathogenesis ofAlzheimer’s Disease. . . . . . . . . . . . 617

Axonal Defects and the Pathologyof Alzheimer’s Disease . . . . . . . . . 618

Impairments in Axonal Transportand the Pathogenesis ofAlzheimer’s Disease. . . . . . . . . . . . 619

INTRODUCTION

Effective communication between the cellbodies and presynaptic terminals of neuronsrequires reliable and timely movement ofAxonal cargo: any

molecule ororganelletransported withinaxons

essential neuronal “cargoes” to their finaldestinations. Such cargoes include vesiclescontaining synaptic proteins, growth factors,signaling molecules, and ion channels. In ad-dition, defined organelles such as endosomesand mitochondria are continuously trans-ported within axons. Finally, protein com-plexes including proteins controlling cyto-plasmic signaling, structure, and degradation

are also actively transported within axons.Whereas some of these cargoes reside in ax-ons where they play structural and other roles,other cargoes participate in a variety of neu-ronal activities such as synaptic plasticity andneurotransmission. Recent findings implicatemany such axonal cargoes in disease pro-cesses and suggest the existence of interplaybetween axonal transport, damage signaling,synaptic plasticity, and diseases of the nervoussystem.

The past decade has seen an explosion inour knowledge of molecules involved in ax-onal transport. At the same time, there hasbeen a dramatic expansion in the identifica-tion of molecules that may cause diseases ofthe nervous system. Not only are these twosets of molecules beginning to overlap, but ac-cumulating evidence suggests that many suchdisorders affect axonal transport during thecourse of disease, perhaps at the earliest orcausative stages. Although such disorders mayvary in their ages of onset, the anatomical sub-strates affected, and the clinical symptoms andsigns produced, they may share failures of ax-onal transport, which may provide opportu-nities for common therapeutic interventions.Dendrites may also be prone to similar de-fects, but for a variety of technical reasons thispossibility has not been as well explored. Thisreview focuses on work in axons, recognizingthat similar issues may pertain to dendrites aswell.

AXONAL TRANSPORT

Overview of Axonal Transport

Studies of axonal transport began with theobservation that nerve cell bodies gener-ate single, thin, nonbranching axis cylinders,which could be readily distinguished frommultiple, highly branched protoplasmic pro-cesses. Shortly thereafter, axis cylinders be-came known as axons, and protoplasmic pro-cesses as dendrites, and their cytoplasmiccontinuity with the cell bodies was es-tablished. The realization that axons and

608 Stokin · Goldstein

Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

dendrites were integral parts of neurons andneuronal circuits led to the suggestion thatinterruption between cell bodies and ax-ons, and a resulting loss of trophic sup-port, could account for the degenerationof fibers in the peripheral stump of a sev-ered spinal nerve. This in turn led to thehypothesis that trophic material must betransported through axons to and from thecell bodies to maintain their structure andfunction.

Support for the proposal that active trans-port occurred in axons came from early studiesof viral spread within neurons. Subsequentnerve constriction studies provided directsupport for this hypothesis by demonstrat-ing continuous transport of biological mate-rial along the axons (1). An explosion of workeventually culminated in the demonstrationof anterograde axonal transport by radiola-beling cargo proteins in axons and of retro-grade axonal transport by studying the uptakeof horseradish peroxidase. This work revealednot only the bidirectional nature of axonaltransport, but also established that axonal car-goes travel at different velocities with fast ax-onal transport occurring at speeds of circa (ca.)100–400 mm/day (ca. 1.0–5.0 μm/s) and slowaxonal transport at speeds of ca. 0.3–3 mm/day(ca. 0.004–0.04 μm/s). The finding that mi-crotubules are the major tracks or “highways”for long-distance axonal transport emergedfrom experiments where microtubule assem-bly was chemically disrupted, which resultedin abrogation of axonal transport and pro-vided direct evidence for the involvement ofmicrotubules (2). Clues regarding the mecha-nism of such transport emerged from the de-termination of microtubule polarity, which inaxons is highly organized so that microtubuleshave their plus ends oriented toward distal ax-ons and presynaptic sites. These findings weresoon followed by the identification of motorproteins that recognize microtubule polaritysuch as kinesin-1 and dynein, which transformchemical energy into mechanical movementtoward microtubule plus and minus ends,respectively.

Neurodegenerativedisorder: disordercharacterized byprogressive neuronalloss

KHC: kinesin heavychain

KLC: kinesin lightchain

Proteins Required for AxonalTransport

Microtubules serve as tracks along which mo-tor proteins such as kinesins and dyneinsgenerate long-distance transport. Micro-tubules are also decorated with microtubule-associated proteins, which may modulate mi-crotubule nucleation and elongation as well ascontrol characteristics of motor protein trans-port. For example, there is compelling evi-dence that the tau protein, whose misbehavioris a prominent feature in many neurodegener-ative disorders, can play a role in controllingmotor protein–driven vesicle transport alongmicrotubules (3).

Compelling evidence suggests that mo-tor proteins play a pivotal role in both fastand slow microtubule-based axonal trans-ports. Microtubule plus end–directed or an-terograde axonal transport is thought to relylargely on the kinesin superfamily of motorproteins, which are currently divided into14 families based on their sequence simi-larities (4). Strong evidence suggests mem-bers of the kinesin-1 (KIF5), -2 (KIF3), -3(KIF1), -4 (KIF4), and -13 (KIF2) familiesparticipate in axonal transport; among them,kinesin-1 is the best studied. Structurally,kinesin-1 is a heterotetramer composed oftwo kinesin heavy chain (KHC) and two ki-nesin light chain (KLC) subunits (Figure 1).KHCs (KIF5A, KIF5B, and KIF5C) con-tain microtubule- and nucleotide-bindingsites in their NH2-terminal motor heads,alpha-helical coiled-coil stalks in the center,and globular COOH termini that interactwith KLC and perhaps with cargoes. KLCs(KLC1, KLC2, and KLC3) contain NH2-terminal heptad repeat regions, which proba-bly form alpha-helical coiled coils and medi-ate interactions with KHC. KLCs also containCOOH-terminal tetratrico peptide repeatsthat appear to be involved in cargo bindingand in the regulation of transport. KIF5Band KLC2 are ubiquitously expressed; KIF5Aand KIF5C are restricted in expression tobrain and other neuronal tissue; and KLC1

www.annualreviews.org • Axonal Transport and AD 609

Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

DHC

DLIC

DIC

Roadblock

LC8

Tctex1

KHC

KLC

Microtubules

– +

Figure 1Schematic structure of anterograde and retrograde motor proteins.Abbreviations: DHC, dynein heavy chain; DIC, dynein intermediatechain; DLIC, dynein light intermediate chain; KHC, kinesin heavy chain;KLC, kinesin light chain.

expression is enriched, but not restricted tothe nervous system. Genetic manipulationof kinesin-1 subunits in combination withnumerous in vitro experiments revealed animportant role of kinesin-1 in axonal trans-port (5–8), although knowledge of the specifictransport functions carried out by the variouskinesin-1 subunits is still needed.

In contrast to anterograde axonal trans-port, which takes advantage of several dif-ferent kinesin motor proteins, a wealth ofdata suggests that dynein may be the ma-jor motor protein powering microtubule mi-nus end–directed or retrograde axonal trans-port. Dynein is a multiprotein complexcomposed of two heavy chains and sev-eral intermediate, light intermediate, andlight chains (Figure 1). Dynein heavy chainsharbor microtubule- and nucleotide-bindingsites within large COOH-terminal motorheads and NH2-terminal stemlike coiledcoils. Dynein intermediate chains contain β-propeller group protein sequences and par-ticipate in the interaction with dynein heavy

chains, dynein light chains, the dynactin com-plex, and perhaps cargoes. Dynein light in-termediate chains and dynein light chains(Tctex1/rp3, roadblock, LC8) are thought toplay a role in dynein-dynein and dynein-cargo interactions via ATP-binding loop mo-tifs and amphiphilic alpha-helical segments,respectively. Dynein-mediated axonal trans-port is thought to be regulated by its interac-tion with the dynactin complex, which con-sists of several proteins including p150Glued,p62, p50-dynamitin, the actin-related proteinArp1, actin, actin capping protein α and β

subunits, p27, p25, and p24. Although manydetails remain to be elucidated, in vivo andin vitro studies suggest that disruption of thedynein/dynactin complex results in a strikingaxonal phenotype (9, 10).

Mechanisms of Axonal Transport

Considerable effort has gone into elucidat-ing the mechanisms by which motor pro-teins generate force and movement along mi-crotubules (11, 12). There are, however, twoprinciples of motor protein mechanism thatmay play major roles in axonal transport bi-ology. The first principle relates to the pro-cessivity of individual molecular motor pro-teins. A large body of evidence suggests thatfor highly processive motor proteins such askinesin-1, the number of motor proteins ona moving cargo does not change the veloc-ity of movement but does change the prob-ability of pausing or stalling during trans-port (13). In contrast, for poorly processivemotor proteins such as dynein, motor num-ber has a large influence on velocity as wellas on the probability of pausing or stalling.Thus one expects the regulation of kinesin-1or dynein motor number on moving car-goes to have different effects on the proper-ties of flux and transport in axons. For ex-ample, decreasing kinesin-1 is predicted tochange pause frequencies or perhaps the bal-ance of anterograde and retrograde transport,but not velocity. This prediction has been


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

experimentally observed (14). The secondprinciple relates to the question of whethersingle-headed motor proteins can generateforce and movement. For example, kinesin-1 consists of two KHCs and contains twoidentical motor domains. Because its mo-tor heads are interconnected by a coiled-coilstalk, they cooperate in a coordinated man-ner to achieve efficient processive movementalong microtubules. In contrast, KIF1A lacksan extended predicted coiled-coil stalk do-main and appears to be monomeric in itsnative state. Although researchers have pro-posed that KIF1A is capable of processivemovement in its monomeric state by ex-changing its microtubule-binding loops in acyclic interaction with microtubules duringeach ATP cycle (15), mounting evidence sug-gests that, to be efficiently processive, KIF1Amonomers undergo a cargo-mediated transi-tion to homodimers that move by a mech-anism akin to that proposed for kinesin-1(16, 17). Thus, cargo interaction may activatesome motor proteins by stimulating multi-merization needed for processive movement.

Most cargo transport in axons may be gen-erated by motor proteins attaching to vesicles,organelles, or protein complexes and mediat-ing movement along stationary microtubules.However, at least two additional mechanismsof motor protein–generated, microtubule-dependent axonal transport have been sug-gested to generate the array of movementsobserved. One mechanism may use station-ary motor proteins attached to nonmotile ax-onal membranes to produce directed move-ment of microtubules and associated cargoes.In this mechanism, plus end–directed move-ment of microtubules and bound cargoes canbe generated by minus end–directed motorproteins, and minus end–directed movementscan be generated by plus end–directed mo-tor proteins (18, 19). Another mechanism de-rives from the observation that some mo-tor proteins can attach simultaneously to twoindependent microtubules. In this case, plusend–directed motor activity between parallel

microtubules will generate plus end–directedmovements; minus end–directed movementscould be generated by a minus end–directedmotor activity (20). In addition to the vari-ety of data supporting these proposed mech-anisms, considerable evidence suggests thatin vivo several kinesin and dyneins work co-operatively to achieve cargo movement (21).How these cooperative interactions fit intothe overall geometry of force generation inaxons remains to be elucidated. Finally, sev-eral relatively recent observations suggest that“fast” motor proteins such as kinesin-1 maybe responsible for slow axonal transport. Ge-netic manipulation of kinesin-1 subunits re-vealed that removal of a specific KHC subunitcalled KIF5A produced defective transport ofneurofilaments, which are known to be trans-ported by slow axonal transport (5). Indeed,in vivo imaging of neurofilament movementrevealed these “slow” cargoes can travel inter-mittently at fast rates, but with slow averagevelocities owing to prolonged pauses and bidi-rectionality of movement (22).

Regulation of Axonal Transport

Regulation of kinesin and dynein activitiesand thus regulation of axonal transport re-main poorly understood. In principle, regula-tion can occur at one of several steps includingcargo recognition and binding by the motorprotein, velocity and character of transport it-self, and recognition of the correct destinationby the motor-cargo complex. Indeed, accu-mulating evidence suggests that kinesin-1 maybe regulated directly by cargo binding suchthat motor activation is coupled to the bind-ing of the motor to vesicles and/or organelles(23–25). Similarly, as described above, at leastone class of kinesin motor proteins may beactivated by the clustering of phosopholipids,which facilitate dimerization required for pro-cessive movement (16).

Among the many cargoes and bind-ing partners identified for anterograde andretrograde motor proteins are several whose


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

Amyloid precursorprotein (APP): typeI glycoprotein thatgives rise toamyloid-β peptides,when appropriatelycleaved, and plays animportant role in thedevelopment ofAlzheimer’s disease

JIP:JNK-interactingprotein

GSK3β:glycogen-synthasekinase 3β

PS1: presenilin-1

Alzheimer’s disease(AD): clinically themost frequentdementia,pathologically aneurodegenerativedisordercharacterized bysenile plaques andneurofibrillarytangles

Microtubule tracks:a polymer of linearlyarrangedα/β-tubulinheterodimers

identities suggest possible mechanisms ofregulation. Such candidates include amyloidprecursor protein (APP) (26) and thegroup of c-Jun NH2-terminal kinase (JNK)-interacting proteins 1, 2, and 3 (JIP1, JIP2,and JIP3/Sunday driver) (27). These proteinsare directly connected to kinase and proteasesystems, among others. Additional evidencesuggests important roles of phosphorylationin motor protein regulation, including per-haps the action of glycogen-synthase kinase3β(GSK3β), presenilin-1 (PS1), and cyclin-dependent kinase 5.

AXONAL TRANSPORT, AGING,AND DISEASE

Many lines of evidence raise the possibilitythat failures in axonal transport play a role ina variety of neurodegenerative diseases. Thisevidence comes from study of the transportmachinery during aging, reports of a variety ofaxonal defects that could be caused by trans-port problems in a number of neurodegen-erative disorders, the realization that manyproteins implicated in disease are activelytransported, and the demonstration that someneurodegenerative diseases can be caused bymutations in genes encoding likely compo-nents or regulators of the transport machin-ery. In the case of Alzheimer’s disease (AD),new evidence is emerging that links pro-teins implicated in disease causation to axonaltransport. In all of these cases, it remains un-clear where in the timing of disease progres-sion transport failures emerge and what rolesuch failures play in progression versus cau-sation. We review this evidence below begin-ning with aging and diverse neurological dis-eases and ending with a discussion of theseissues in the context of AD.

Axonal Transport and Aging

Aging has become an an intensely studied is-sue as a result of the increased prevalence ofpeople reaching advanced age and the result-

ing increase in the incidence of diseases re-lated to advanced age such as atherosclerosisand AD. Surprisingly, however, relatively littleis known about how axons and axonal trans-port perform during aging and whether suchchanges might predispose some people to thedevelopment of aging-related diseases suchas AD. Most studies thus far have examinedthe effects of aging either on axonal compart-ment structure or on axonal transport rates.Several studies reported age-related reductionin axonal microtubules (28), shifts in the dis-tribution of microtubule-associated proteinssuch as tau and neurofilaments (29, 30), andthe appearance of axonal accumulations ofproteins such as APP (31) and other mate-rials such as glycogen and lipofuscins. Per-haps the most obvious and direct evidence forage-related changes within axons is providedby the observation of progressive increases inthe number of focal axonal swellings with age(32). These are reminiscent of similar age-related accumulations of APP (31). Intrigu-ingly, some of these changes resemble thosefound in the Klotho mice, which recapitu-late several characteristics of premature aging(33). The substantial structural changes seenin axons with aging may hamper efficient ax-onal transport. This view is consistent with anumber of radiolabeling experiments, whichshowed significant reductions in anterogradetransport of axonal vesicles, various proteins,phospholipids, and steroid hormones. Reduc-tions in the retrograde axonal transport ofaxonal vesicles, neurotransmitter-related pro-teins, growth factors, and steroid hormonesand in the slow axonal transport of tubulin,neurofilaments, and synuclein have also beenreported. The mechanisms underlying theseage-related changes in axonal structure andtransport remain obscure. In particular, it re-mains unknown whether these changes affectall transported proteins uniformly and thusmight be a result of changes in the micro-tubule tracks or, alternatively, whether agingprimarily affects only certain pathways (34)while sparing others.


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

Impairments in Axonal Transportand the Pathogenesis ofNeurodegenerative Diseases

A number of neurodegenerative disordersappear to be caused by genetic defects ingenes encoding proteins that play a directrole in axons and axonal transport. For ex-ample, Charcot-Marie-Tooth disease type IIhas been linked to mutations in genes encod-ing KIF1β(35) and the low molecular weightneurofilament protein (36). Similarly, muta-tions in the KIF5A gene are found in heredi-tary spastic paraplegia (37), and mutations inthe p150Glued gene are found in amyotrophiclateral sclerosis (ALS) (38) and distal spinalbulbar muscular atrophy (39). These data cor-roborate results from studies with spastin (40),which support the hypothesis that impairedaxonal transport could play a major role inthe pathogenesis of hereditary spastic paraple-gia. In addition, the identification of mutantp150Glued as a cause of ALS adds genetic sup-port to the reported axonal defects and impair-ments in axonal transport in the pathogene-sis of ALS. Intriguingly, dynein mutations cansuppress ALS caused by mutant SOD in mice(41).

Genetic and cell biological evidence alsoimplicate defective axonal transport in thepathogenesis of movement disorders such asHuntington’s disease (HD). Although the ex-pansion of CAG repeats in the gene encod-ing huntingtin is well established as the causeof HD, the mechanism(s) causing neurode-generation and neurological defects remain(s)unknown. Some insights have emerged fromreports that implicate the huntingtin proteinin normal functions of the transport machin-ery. These findings are intriguing in light ofreports suggesting that mutant huntingtin,and polyglutamine proteins in general, cancause impaired axonal transport and inducethe formation of axonal protein aggregates insquid (42), fruit fly (43), and mammalian (44)HD. These observations together can accountfor the overt synaptic and axonal pathologyin HD. Whether such a mechanism can ac-

Dementia:progressive declinein two or morecognitive functionsthat does not perturbconsciousness,significantly affectsindependenteveryday living, andis not caused byother known illnesses

count for the preferential death of some celltypes in HD as well as defects seen in otherpolyglutamine diseases remains to be seen. Atleast some of the ataxin genes encode pro-teins whose normal functions are nuclear, sug-gesting nuclear pathology may be primary inat least some of these disorders. Compellingexperimental evidence in mouse models ofspinocerebellar ataxia type 1 (45) supports thisview. Comparable phenomena may be partof the pathogenesis of at least one form ofearly onset dystonia. Intriguingly, in the caseof early onset dystonia linked to mutations inthe AAA+ protein torsin A, a pathogenic mu-tation that encodes a mutant torsin A lackinga glutamic acid residue in the COOH terminihas been reported to interrupt the binding oftorsin A to KLC1 and result in its deficienttransport (46).

With respect to the pathogenesis of someof the major dementias, a genetic associa-tion between abnormalities in the tau geneand some forms of fronto-temporal demen-tias, Pick’s disease, corticobasal degeneration,and progressive supranuclear palsy is well es-tablished (47) and consistent with the proposalthat defective tau function may cause defectsin the assembly and stability of microtubulesin turn leading to defective axonal transport.Similar changes in tau biology can cause ab-normal axonal transport in cell culture includ-ing defective peroxisomal transport, perhapsleading to sensitivity to oxidative damage (3).Transport defects are also seen in tau animalmodels (48), although the precise mechanismsremain unknown. Intriguingly, abnormalitiesin tau protein are found diffusely in AD andrepresent one of its pathological hallmarks.Although the genetic associations between tauand AD are tentative, the biological roles oftau suggest that cytoskeletal defects and failedaxonal transport can contribute to the patho-genesis of common dementias.

In summary, genetic and functional studiesprovide strong evidence for the involvementof impaired axonal transport in the pathogen-esis of several neurodegenerative disorders.


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

DAI: diffuse axonalinjury

TBI: traumaticbrain injury

Aβ: amyloid-βpeptide

Whether other disorders such as KIF21defects in congenital fibrosis of the extraocu-lar muscles type 1 and defects in KIF13 linkedto schizophrenia have similar origins remainsto be determined.

Impaired Axonal Transportas a Result of Diseases

Although axonal transport is not obviouslycausally related to the onset of many diseasesof the nervous system, these diseases appearto affect, perhaps indirectly and significantly,axonal structure and transport. Understand-ing the mechanisms underlying axonal insultin these diseases may provide valuable cluesfor the development of new diagnostic as-says and therapeutics. Examples of diseaseswhere significant advances in understandingthe mechanisms of axonal injury have beenachieved are diffuse axonal injury (DAI) anddemyelinating diseases.

DAI is a consequence of traumatic braininjury (TBI) and an epigenetic risk factor forAD. In DAI, a massive accumulation of APPand its potentially toxic proteolytic product,amyloid-β peptide (Aβ), takes place withinswollen axons at injury sites. This finding isintriguing given the strong evidence that APPcontributes to the pathogenesis of AD andthat TBI is a risk factor for AD. Recent worksuggests that impaired axonal transport as aresult of TBI (49) can cause long-lasting ac-cumulations of APP, its proteolytic machin-ery, and kinesin-1 within axonal swellingsthat contain intra-axonal Aβ. Release of ax-onally generated Aβ into the extracellularspace may contribute to amyloid deposition inDAI.

Researchers have also proposed that ax-onal damage and loss may be responsible forthe persistent neurological deficits observedin patients with demyelinating diseases suchas multiple sclerosis and acute disseminatedencephalomyelitis. APP accumulation withindamaged axons also occurs in demyelinatingdiseases (50). Nevertheless, little is known

about the mechanism by which axonal seg-ments adjacent to compromised oligodendro-cytes incur injury. Whereas an autoimmunedestruction of the myelin sheaths surround-ing axons and compromised conduction prop-erties of the denuded axons are widely ac-cepted, recent studies offer new insights intothe mechanisms responsible for the accom-panying axonal defects. Although the mech-anisms remain to be clarified, these studiesshow that oligodendrocytes deficient in themyelin proteolipid protein (51) as well as ac-tivated microglia (52) can both cause impairedfast axonal transport.

That APP and Aβ accumulate within dam-aged axons in several diseases suggests thatAPP may represent a surrogate marker of ax-onal pathology. Thus APP and/or Aβ may besusceptible to reductions in axonal transportor play a general role in axonal repair or re-generation. Intriguingly, studies of Niemann-Pick type C disease provide another linkbetween impaired axonal transport, axonaldefects, and Aβ generation. In brief,Niemann-Pick disease type C is charac-terized by intracellular accumulation ofunesterified cholesterol within the endocyticpathway, endosomal abnormalities, andwell-described axonal defects. Coincidently,experimental models of Niemann-Pick dis-ease type C exhibit impaired axonal transportof endogenously synthesized cholesterol,accumulations of APP and PS1, and aberrantgeneration of Aβ (53, 54). These studiessupport the view that deficient transport canplay an important role in the generation ofAβ and are consistent with the findings fromDAI studies.

AXONAL TRANSPORT ANDALZHEIMER’S DISEASE

That the observed pathological changes in ADare at least partly the result of abnormal axonaltransport has been discussed for decades (55).However, until recently, too little was knownabout the axonal transport machinery to


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

critically test these ideas. Here we summarizethe major features of AD, the axonal transportand functions of AD-related molecules, andaxonal defects seen in AD. We then discusshow a cascade of axonal blockages could causethe pathogenesis of AD.

Overview of Alzheimer’s Disease

AD was first described in a report that associ-ated bizarre psychiatric symptomatology withthe postmortem observation of senile plaquesand neurofibrillary tangles. Senile plaqueswere later described to consist of a networkof dystrophic neurites embedded in extracel-lular, congophilic, and fibrillar amyloid (56).These neuritic changes and amyloid depositsare commonly accompanied by a prominentglial reaction. At about the same time neu-rofibrillary tangles were found to correspondto intracellular accumulations of paired heli-cal filaments (57). AD is the most common de-mentia with senile plaques and neurofibrillarytangles as pathological hallmarks when foundin diagnostically relevant brain regions (58,59). In addition, AD brains generally exhibitsevere perturbations of several neurotrans-mitters and widespread synaptic and neuronalloss in distinct anatomic areas such as the lim-bic system and the basal forebrain (60–63).These changes are accompanied by a severedisruption of the axonal as well as dendritic cy-toskeleton, which suggests failed axonal trans-port at some point in the progression of thedisease.

To date, mutations in three independentgenes have been found to segregate with kin-dreds afflicted by rare familial AD (FAD). Thefirst gene emerged from studies focused onthe purification and sequencing of proteinsfound in amyloid deposits (64). These stud-ies identified Aβ as the major constituent ofamyloid, which led to the identification ofthe precursor protein, APP (65–67). A num-ber of mutations in the human gene-encodingAPP were found to cause some forms of FAD,perhaps as a result of aberrant Aβ genera-

Senile plaque: anetwork ofdystrophic neuritesembedded inextracellular,congophilic, andfibrillar amyloid

Neurofibrillarytangle: intracellularpaired helical(twisted) filamentsthat form as a resultof abnormal hyper-phosphorylation oftau

BACE: β-site APPcleaving enzyme

tion (69, 70). In addition, the mapping ofAPP to chromosome 21, which is trisomic inDown’s syndrome, provided a possible causefor the AD pathology consistently observedin the brains of Down’s syndrome patients.Further genetic studies identified mutationsin PS1 and presenilin-2 (PS2) as additionalgenetic causes of FAD (71). The finding thatmutations in PS1 and PS2 also lead to aber-rant Aβ generation was an important clue fordeciphering the mechanism of Aβ formationand led to the discovery that presenilins arelikely key components of the proteolytic pro-cessing machinery for APP and other pro-teins such as Notch (72). In fact, a combi-nation of results from many studies revealedthat Aβ formation can be either abrogatedor stimulated by the proteolytic processingof APP. Cleavage of APP within the Aβ do-main of APP (α-cleavage) abrogates Aβ for-mation, whereas sequential cleavage of APPat the N termini (β-cleavage) and C termini(γ-cleavage) of the Aβ domain of APP re-sults in Aβ formation (Figure 2) (65, 73).Members of the disintegrin and metallopro-teinase families were identified as participantsin the α-cleavage, and the β-site APP cleav-ing enzyme (BACE) as a participant in the β-cleavage, whereas nicastrin, anterior-pharynxdefective protein-1 and presenilin enhancer-2, along with PS1, orchestrate the γ-cleavageof APP. Finally, apolipoprotein ε4 alleles werefound to be associated with earlier onset andmore aggressive forms of AD. These find-ings, together with the discovery that ab-normally hyperphosphorylated tau forms theneurofibrillary tangles (74), provide a frame-work for understanding the molecular basisof AD.

The genetic and biochemical data, com-bined with the observation that amyloidplaques are a characteristic feature of AD, ledto the formulation of the amyloid-cascade hy-pothesis (75–77). In its simplest form this hy-pothesis suggests AD develops as a result ofeither increased production of Aβ through-out life owing to FAD mutations or owing to


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

N CFull-length APP

C99C83

p3

Nonamyloidogenic Amyloidogenic

Figure 2Major proteolyticprocessingpathways ofamyloid precursorprotein.Abbreviations:ADAM, adisintegrin andmetalloproteinase;APP, amyloidprecursor protein;BACE, β-site APPcleaving enzyme;PS1, presenilin-1.

a gradually increasing buildup of Aβ as aresult of failed mechanisms of Aβ clear-ance thought to occur in sporadic AD cases.These events are proposed to result inaccumulation, oligomerization, and deposi-tion of Aβ. Aβ oligomers or deposits arethought to activate microglia, trigger an in-flammatory response, and alter synaptic struc-ture or functions. These events might inturn give rise to altered neuronal home-ostasis, altered kinase and phosphatase ac-tivities, the formation of neurofibrillary tan-gles, and widespread synaptic and neu-ronal dysfunction and loss precipitating indementia.

Although there are clear causative rela-tionships between genes controlling Aβ for-mation and AD, several features of AD arenot well accounted for by the amyloid-cascadehypothesis. A major issue is the apparentlypoor correlation between amyloid depositsand other aspects of the pathology observed

in AD brains (78). For example, an obviousrelationship between senile plaques and neu-rofibrillary tangles is lacking (79). Whereasneurofibrillary tangles start forming in the en-torhinal region and then spread toward thecortices, the opposite appears true for senileplaques (80, 81). Similarly, synaptic numbersare generally not consistently affected by amy-loid deposits in animal models of AD, anddata establishing a role for Aβ in decimat-ing synaptic and neuronal numbers in vivo arelacking. In addition, neuronal loss in AD of-ten occurs independently and in anatomicallydistant regions from areas of amyloid deposi-tion. Finally, amyloid burden is not well re-lated to the clinical picture of AD. For ex-ample, significant amounts of amyloid can befound deposited in the brains of cognitivelyintact subjects (82). Amyloid burden in ADbrains is variable and does not predict eitherthe duration or severity of AD. Furthermore,many of the symptoms observed in AD result


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

from damage to brain areas often devoid ofamyloid deposits.

Axonal Transport of Proteins Linkedto the Pathogenesis of Alzheimer’sDisease

Many proteins associated with the pathogen-esis of AD (including APP, BACE, PS1, nicas-trin, Aph-1, presenilin enhancer-2, synuclein,and tau) have been observed in the axonalcompartment of neurons, with many of themfound at presynaptic terminals (83–86). Thus,transport is almost certainly necessary to de-liver these proteins to their final destina-tions (87). For APP, there is strong evidencefrom cell culture, Drosophila, and mice thatkinesin-1 is responsible for APP transport(26, 88–90). There are also reports that PS1,BACE, and synuclein undergo axonal trans-port at speeds consistent with fast antero-grade axonal transport (91–95), and althoughthere is some controversy (96), APP, BACE,and PS1 have been suggested to travel withinthe same membrane compartment in axons(92, 97–100). Some proposals for the mecha-nism of APP transport suggest the C terminusof APP interacts with the tetratrico repeatsof the kinesin-1 KLCs (26), either directly,but possibly enhanced by JIP1 (101), or in-directly via complex formation with JIP1 (96,102). Intriguingly, APP has also been reportedto undergo fast anterograde axonal transportas a component of the herpes simplex virus-derived viral particles associated with kinesin-1 (103). Further work is required to betterunderstand the mode of interaction betweenAPP and KLCs; to evaluate the mechanismsof axonal transport of BACE, PS1, and othermolecules involved in AD; and to identify ad-ditional partners, such as proteins interactingwith APP tail 1 (104), that might take partin transporting axonal APP. Interestingly, re-cent observations indicated that unlike JIP1and JIP2, which associate and phosphorylateAPP, JIP3 does not associate with APP butmay play a role in regulating its transport andphosphorylation (105).

Axonal Functions of Proteins Linkedto the Pathogenesis of Alzheimer’sDisease

Mounting evidence suggests that many pro-teins implicated in the pathogenesis of ADhave functions in the axonal compartment.For example, early work on the biologicalfunctions of APP suggested a possible rolein promoting axonal growth (106, 107). Infact, several cell-culture studies suggested thatreductions (108, 109), overexpression (110),and other modifications of APP (111) couldcause abnormalities in axonal growth. Simi-larly, deletions (112, 113) or overexpressionof APP (114, 115) in mice both gave rise toreductions in white-matter brain structuresand corroborated cell-culture studies by pro-viding in vivo evidence for a role of APP inthe maintenance of axonal structure and func-tion. These data are consistent with the ob-served upregulation and axonal enrichmentof APP during nervous system developmentand in axonal injury states when moleculesinvolved in axonal growth are expected to bemost active (106, 116). Of particular interestin this context are reports of axonal increasesin APP in several disease states that exhibit ax-onal injury. These disease states include mul-tiple sclerosis, TBI, brain infarctions and in-fections, and neurodegenerative diseases suchas Creutzfeldt-Jakob’s or AD. These observa-tions therefore suggest APP may play an im-portant role during axonal repair. This con-jecture is supported by recent experiments inDrosophila indicating a role of the DrosophilaAPP-like (APPL) gene in recovery from braininjury (116). APP accumulation within axonsin disease states could also be the result of ab-normal or continued axonal transport in thepresence of axonal blockages.

Recent work in mice suggests that APPmay play a role within the axonal compart-ment by participating in axonal transport(92, 117). Although controversial (96), thisproposal is based on the initial observationthat reduction or overexpression of APP inDrosophila (90, 118) causes axonal transport


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

deficits reminiscent of those observed in mo-tor protein mutants (119). Similar defects havebeen observed in mice overexpressing APP(120) and in AD (14). Finally, axonal trans-port deficits caused by APP overexpressionin Drosophila and mice can be enhanced byotherwise benign reductions of kinesin-1 (14,90). Consistent with these data are the find-ings that synapses in flies and mice deficientin APP exhibit reduced numbers of synapticboutons (121–123).

In addition to a role in APP processing,some evidence suggests that both PS1 andBACE possess additional functions within theaxonal compartment. Similar to APP, manip-ulations of PS1 in cell-culture systems re-veal a role in axonal growth and morphology(124–127), which has been shown to be im-portant in development of the nervous sys-tem (126, 128) and in states of axonal in-jury (99). Examination of the means by whichPS1 exerts its functions in the axonal com-partment suggests several mechanisms rang-ing from direct (126, 129) to indirect actions(130) on the axonal cytoskeleton. Intimate in-volvement in the control of the axonal trans-port machinery via phosphorylation of KLCby GSK3β (131, 132) may also occur. Intrigu-ingly, PS1 may also control the transport ofAPP and other proteins, possibly via GSK3β

(133, 134). These ideas are consistent with awealth of data that, although disputed (135),suggest that APP and PS1 interact (136–139).Although less is known about BACE, its over-expression produces overt axonal degenera-tion (140) and results in reduced axonal trans-port of APP (141). More specifically, BACEoverexpression may shift β-cleavage of APPto the cell bodies, which results in inappropri-ate post-translational modifications of APP, inreduced targeting of APP into the axonal com-partment, in reduced axonal transport of APP,and in diminished Aβ generation (141). In-triguingly, tau has also been proposed to regu-late kinesin-1-mediated vesicle and organelletransport along microtubules as well as or-ganizing axonal microtubules. Related rolesin axonal transport may unite tau-related and

APP-related pathologies in AD, perhaps viainteractions including JIP1 and GSK3β (3,52, 142). Such a view is consistent with thereported colocalization of APP, BACE, PS1,and Aβ in swollen axons induced by diffuseaxonal injury (99).

Axonal Defects and the Pathology ofAlzheimer’s Disease

Years of pathological examination of ADbrains have yielded many descriptions of ab-normal axons. These axonal defects may re-flect transport problems and can be dividedinto three classes: (a) those juxtaposed to amy-loid within senile plaques; (b) those associ-ated with neurofibrillary tangles, and (c) thosespatially distinct from the hallmark lesionsof AD.

First, dystrophic axons juxtaposed to amy-loid are the best studied and are found as-sociated with dense amyloid cores as well aswith smaller amyloid bundles. Some workershave proposed that these dystrophic axons aremore specific to AD than the amyloid itself(143). Some evidence suggests that amyloid-associated dystrophic neurites are best distin-guished based on whether they harbor ab-normally phosphorylated tau (144). In fact,most such axons are immunoreactive to ax-onal cargo proteins such as synaptophysinor tau (144, 145). In addition, a subpopula-tion of abnormal axons found adjacent to theamyloid was identified to accumulate actin,actin-depolymerizing factor, and cofilin (146).Overall, the tight relationship between amy-loid and abnormal axons indicates that eitheramyloid underlies the formation of axonal de-fects or that axonal defects represent “hotspots” implicated in the amyloid depositionor both.

Second, abnormal axons associated withneurofibrillary tangles in AD are well de-scribed (147). Abnormal thin and tortuousaxons immunoreactive to a battery of differ-ent phospho-tau epitopes represent an invari-able feature of AD brains. These axons can befound in areas either spatially distinct from,


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

or adjacent to, the amyloid deposits and neu-rofibrillary tangles. Although massive disor-ganization of the axonal compartment by theabnormally phosphorylated tau is associatedwith an abnormal microtubule network, it isunclear whether this can be accounted for bythe action of abnormal tau (28). Interestingly,evaluation of abnormal axons associated withneurofibrillary tangles suggests that at leastsome of these are not related to amyloid (148).These tangle-associated neuritic clusters areenriched in tau and form dense aggregatesand ghost tangles with the core made up ofextracellular bundles of straight filaments. Al-though the significance of tangle-associatedneuritic clusters in AD remains largely un-explored, the clusters provide important evi-dence that amyloid is not necessarily presentin axonal defects at all stages and, alternatively,that amyloid is not required for the formationof some populations of abnormal axons en-countered in AD brains.

Third, abnormal axons spatially distinctfrom the hallmark lesions of AD consist ofshorter, more irregular, and tortuous pro-cesses (14, 149). These are most evident asfocal axonal swellings that correspond to ab-normal accumulations of axonal cargos andtransport proteins (14). These swellings ex-hibit aberrant phosphorylation of neurofila-ments but not of tau. They form early inAD and precede tau-immunoreactive axonsspatially distinct from amyloid deposits andneurofibrillary tangles. Importantly, becauseabnormal axons form in brain areas that even-tually develop hallmark lesions of AD, it isplausible they represent precursor lesions tothose observed associated with amyloid andtangles.

Several studies reported axonal loss inbrain regions typically afflicted by AD (150)and also in the olfactory and optic nerves,which are readily amenable to axonal quan-tification (151–153). Similarly, in vivo imag-ing studies of brains from AD patients showedselective white-matter changes (154, 155).These studies are consistent with the vari-ety of axonal defects observed in AD brains

and with the clinical disconnection syndromedemonstrated in subjects afflicted by AD(156).

A number of animal models expressingAD-related proteins exhibit a variety of axonaldefects akin to those observed in AD. Intrigu-ingly, these defects were observed not onlyin models based on molecules tightly linkedto AD such as tau, APP, BACE, or PS1 (14,140, 157, 158), but also in models based onmolecules more distantly related to AD suchas p25 and apolipoprotein ε4. In Drosophila,overexpression of APP alone or of APP andtau resulted in axonal defects reminiscent ofthose observed in Drosophila motor proteinmutants (90, 118). Comparison of dystrophicneurites juxtaposed to amyloid in AD brainswith those in brains of mouse models of ADalso revealed striking similarities (159). In-triguingly, similar dystrophic axons could befound in areas devoid of amyloid or neurofib-rillary tangles in AD (14). Therefore the for-mation of axonal defects may not require thepresence of amyloid- or tau-related changesalthough these pathologies may modify or en-hance axonal abnormalities.

Impairments in Axonal Transportand the Pathogenesis of Alzheimer’sDisease

There is a considerable amount of data consis-tent with the hypothesis that impaired axonaltransport plays a crucial role in the pathogen-esis of AD (55). These data include the consis-tent observation of widespread axonal pathol-ogy in AD including abnormal axons that ex-hibit aberrant accumulations of APP (160)and its metabolites (161, 162); synapse- (163),endocytosis- (164), and neurotransmitter-related proteins (14, 165); resident axonal pro-teins such as neurofilaments and tau; glycogen(166); and organelles (167), in addition to thesequestration of tubulin (168); reduced num-ber of microtubules tracks (28); and the emer-gence of abnormal filaments (169). Theseabnormal axons appear to comprise an im-portant component of the dystrophic neurites


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

that constitute senile plaques and, therefore,correspond to an essential pathological com-ponent of AD. The observation that develop-ment of axonal abnormalities in some brainregions precedes the rest of known AD pathol-ogy, whereas in others it occurs in spatiallydistinct areas from the rest of the known ADpathology, together with the finding that ab-normal axons form at least one year prior toamyloid deposition in some mouse models(14), suggests the production of axonal de-fects could coincide with the earliest stagesof AD pathogenesis. Intriguingly, reductionsin kinesin-1 motor proteins promote the de-velopment of axonal defects in Drosophila (90,118). In mouse similar kinesin-1 reduction en-hances the development of axonal defects, in-creases aberrant Aβ generation, and enhancesamyloid deposition (14, 90). These data sug-gest a causal relationship between failed ax-onal transport and the generation of axonalabnormalities and provide a direct link be-tween changes in axonal transport, aberrantaccumulation or production of Aβ, and theformation of senile plaques. Similarly, sev-eral studies showed that Aβ per se is suffi-cient to induce the formation of axonal ab-normalities (170) and may directly contributeto the impairments in the axonal transport(171, 172). Whether aberrant axonal Aβ gen-eration causes failed axonal transport and ax-onal defects or whether aberrant Aβ gener-ation might be the result of impaired axonaltransport that causes further deterioration ofaxonal transport is unclear.

Abnormal phosphorylation of tau and thecorresponding axonal abnormalities are aninvariable feature of AD that may directlyimpair axonal transport of APP and othermolecules (173). This feature of AD is in-triguing in light of reported improvementsin axonal transport, increased numbers of mi-crotubule tracks, and ameliorated motor im-pairments observed in tau transgenic miceupon treatment with microtubule-stabilizingdrugs (174, 175). Unexpectedly, some mu-tations linked to kindreds afflicted by FADalter axonal transport of axonal cargoes in-

cluding APP (131, 133). This finding pro-vides a link between abnormal processing ofAPP, aberrant Aβ generation, and impair-ments in axonal transport. Several risk fac-tors for AD development including advancedage, apolipoprotein ε status, and repetitivetrauma have all been linked to defects in ax-onal transport. For example, aging may beassociated with reduced axonal transport inanatomically relevant areas to AD, such as inthe basal cholinergic forebrain (176), whereashomozygosity for apolipoprotein ε4 produceswhite-matter changes in asymptomatic sub-jects (177).

We find it striking that impairments in ax-onal transport present an economical explana-tion for the early synaptic changes observedin AD along with the observations that cor-tical levels of nerve growth factor in AD arenormal even though basal forebrain cholin-ergic neurons exhibit features diagnostic ofnerve growth factor deprivation (178, 179).We also think it is relevant that cortical lev-els of cholinergic enzymes are reduced in ADeven though basal forebrain cholinergic neu-rons retain normal expression of choliner-gic markers for some time after disease onset(180). The finding of significant reductionsin axonal transport in postmortem AD brains(181) corroborates these observations as dothe obvious changes in tau and other cy-toskeletal proteins in axons.

We suggest that small initial changes in ax-onal transport pathways or spontaneously oc-curring axonal blockages over time can trig-ger early abnormalities in synaptic and axonalstructure and function and the developmentof sporadic AD. Such impairments might bea consequence of age-related reductions inmicrotubule number or transport, oxidativestress (182), or perhaps traumatic brain in-jury. Impairment of axonal transport couldstimulate Aβ generation (14), which at somepoint cannot be efficiently cleared and startsaccumulating. Abnormal accumulations in Aβ

might induce further deterioration of axonaltransport, more pronounced axonal pathol-ogy, and additional impairments in synaptic


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

function. Importantly, impairments in axonaltransport and aberrant Aβ generation couldmutually potentiate each other in a vicious cy-cle, producing increasing damage over timeincluding perhaps tau abnormalities. Such avicious cycle, consisting of impaired axonaltransport, aberrant Aβ generation, and tauabnormalities, might lead to the formationof paired helical filaments and clusters of ax-onal defects from multiple axons. This wouldmark the beginning of amyloid deposition andthe appearance of neurofibrillary tangles. No-tably, axonal blockages must also hamper ret-rograde axonal transport pathways (183) thatprovide cell bodies with the neurotrophic sig-nals important for the maintenance of theirdifferentiated state and survival (184), whichcould result in neuronal loss.

In FAD, blockages might be initiated byabnormal processing or transport of APP andin Down’s syndrome by abnormal levels ofAPP similar to that reported in Drosophila andin mouse (14, 90). Finally, polymorphisms in

the KLC1 subunit of kinesin-1 have been re-ported to increase the risk of AD (185), al-though large-scale studies are required to con-firm or refute those data.

Although we favor a mechanism in whichdefective axonal transport or age-related de-fects in axonal transport precipitate AD, werecognize that this hypothesis does not ac-count for all features of this disease. For ex-ample, similar to the amyloid-cascade hy-pothesis, an axonal blockage cascade does notexplain the regional selectivity of the dam-age observed in AD. In addition, it does notexplain the apparent lack of peripheral ner-vous system involvement. Furthermore, nohypothesis proposed thus far provides a clearaccount of what triggers the development ofthe prevalent sporadic form of AD. Furtherwork is required to test rigorously the mecha-nisms involved in the pathogenesis of AD andto critically examine whether axonal transportplays a definitive role in the causation or theprogression of AD.

SUMMARY POINTS

1. Many proteins linked to the pathogenesis of neurodegenerative disorders includingAD undergo axonal transport and may be important to maintain not only synapticbut also axonal structure and function.

2. Recent data suggest that impaired axonal transport can promote aberrant Aβ genera-tion and enhance amyloid deposition. Thus, an intimate link between axonal transportand protein deposition in the pathogenesis of AD may exist.

3. Axonal defects are observed early in AD, and APP accumulates in damaged axons inseveral disease and injury states.

FUTURE ISSUES TO BE RESOLVED

1. How is axonal transport regulated and what is the basis for age-related changes inaxonal transport?

2. Are defects in axonal transport a cause or a consequence of the pathological changesin AD?

3. Do genetic variations in AD susceptibility identify genes involved in axonal transportfunctions?


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

DISCLOSURE STATEMENT

L.S.B. Goldstein is a consultant and shareholder for Cytokinetics, Inc. G.B. Stokin and L.S.B.Goldstein hold patents related to transport and AD.

LITERATURE CITED

1. Weiss P, Hiscoe HB. 1948. J. Exp. Zool. 107:315–952. Kreutzberg GW. 1969. Proc. Natl. Acad. Sci. USA 62:722–283. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E. 1998. J.

Cell. Biol. 143:777–944. Lawrence CJ, Dawe RK, Christie KR, Cleveland DW, Dawson SC, et al. 2004. J. Cell.

Biol. 167:19–225. Xia CH, Roberts EA, Her LS, Liu X, Williams DS, et al. 2003. J. Cell. Biol. 161:55–666. Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, et al. 1998. Cell 93:1147–587. Gindhart JG Jr, Desai CJ, Beushausen S, Zinn K, Goldstein LS. 1998. J. Cell. Biol.

141:443–548. Rahman A, Kamal A, Roberts EA, Goldstein LS. 1999. J. Cell. Biol. 146:1277–889. Schroer TA. 2004. Annu. Rev. Cell. Dev. Biol. 20:759–79

10. LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, et al. 2002. Neuron 34:715–27

11. Yildiz A, Selvin PR. 2005. Trends Cell Biol. 15:112–2012. Asbury CL. 2005. Curr. Opin. Cell Biol. 17:89–9713. Spudich JA. 1990. Nature 348:284–8514. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, et al. 2005. Science 307:1282–

8815. Nitta R, Kikkawa M, Okada Y, Hirokawa N. 2004. Science 305:678–8316. Tomishige M, Klopfenstein DR, Vale RD. 2002. Science 297:2263–6717. Rashid DJ, Bononi J, Tripet BP, Hodges RS, Pierce DW. 2005. J. Pept. Res. 65:538–4918. He Y, Francis F, Myers KA, Yu W, Black MM, Baas PW. 2005. J. Cell. Biol. 168:697–70319. Orokos DD, Cole RW, Travis JL. 2000. Cell Motil. Cytoskelet. 47:296–30620. Baas PW, Ahmad FJ. 2001. Trends Cell Biol. 11:244–2921. Kural C, Kim H, Syed S, Goshima G, Gelfand VI, Selvin PR. 2005. Science 308:1469–7222. Wang L, Ho CL, Sun DM, Liem RKH, Brown A. 2000. Nat. Cell Biol. 2:137–4123. Friedman DS, Vale RD. 1999. Nat. Cell Biol. 1:293–9724. Verhey KJ, Lizotte DL, Abramson T, Barenboim L, Schnapp BJ, Rapoport TA. 1998. J.

Cell. Biol. 143:1053–6625. Stock MF, Guerrero J, Cobb B, Eggers CT, Huang TG, et al. 1999. J. Biol. Chem.

274:14617–2326. Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS. 2000. Neuron 28:449–5927. Cavalli V, Kujala P, Klumperman J, Goldstein LS. 2005. J. Cell. Biol. 168:775–8728. Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, et al. 2003. Am. J. Pathol.

162:1623–2729. Niewiadomska G, Baksalerska-Pazera M. 2003. Neuroreport 14:1701–630. Uchida A, Tashiro T, Komiya Y, Yorifuji H, Kishimoto T, Hisanaga S. 2004. J. Neurochem.

88:735–4531. Kawarabayashi T, Shoji M, Yamaguchi H, Tanaka M, Harigaya Y, et al. 1993. Neurosci.

Lett. 153:73–7632. Masuoka DT, Jonsson G, Finch CE. 1979. Brain Res. 169:335–41


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

33. Uchida A, Komiya Y, Tashiro T, Yorifuji H, Kishimoto T, et al. 2001. J. Neurosci. Res.64:364–70

34. Goemaere-Vanneste J, Couraud JY, Hassig R, Di Giamberardino L, van den Bosch deAguilar P. 1988. J. Neurochem. 51:1746–54

35. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, et al. 2001. Cell 105:587–9736. Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, et al. 2000. Am.

J. Hum. Genet. 67:37–4637. Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, et al. 2002. Am. J. Hum. Genet.

71:1189–9438. Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, et al. 2004. Neurology

63:724–2639. Puls I, Oh SJ, Sumner CJ, Wallace KE, Floeter MK, et al. 2005. Ann. Neurol. 57:687–9440. McDermott CJ, Grierson AJ, Wood JD, Bingley M, Wharton SB, et al. 2003. Ann. Neurol.

54:748–5941. Kieran D, Hafezparast M, Bohnert S, Dick JR, Martin J, et al. 2005. J. Cell. Biol. 169:561–

6742. Szebenyi G, Morfini GA, Babcock A, Gould M, Selkoe K, et al. 2003. Neuron 40:41–5243. Gunawardena S, Her LS, Brusch RG, Laymon RA, Niesman IR, et al. 2003. Neuron

40:25–4044. Trushina E, Dyer RB, Badger JD 2nd, Ure D, Eide L, et al. 2004. Mol. Cell. Biol. 24:8195–

20945. Orr HT, Zoghbi HY. 2001. Hum. Mol. Genet. 10:2307–1146. Kamm C, Boston H, Hewett J, Wilbur J, Corey DP, et al. 2004. J. Biol. Chem. 279:19882–

9247. Goedert M, Spillantini MG. 2001. Biochem. Soc. Symp. (67):59–7148. Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, et al. 1999. Neuron 24:751–6249. Stone JR, Okonkwo DO, Dialo AO, Rubin DG, Mutlu LK, et al. 2004. Exp. Neurol.

190:59–6950. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. 2002. Brain 125:2202–1251. Edgar JM, McLaughlin M, Yool D, Zhang SC, Fowler JH, et al. 2004. J. Cell. Biol.

166:121–3152. Stagi M, Dittrich PS, Frank N, Iliev AI, Schwille P, Neumann H. 2005. J. Neurosci.

25:352–6253. Jin LW, Shie FS, Maezawa I, Vincent I, Bird T. 2004. Am. J. Pathol. 164:975–8554. Burns M, Gaynor K, Olm V, Mercken M, LaFrancois J, et al. 2003. J. Neurosci. 23:5645–

4955. Terry RD. 1996. J. Neuropathol. Exp. Neurol. 55:1023–2556. Terry RD, Gonatas NK, Weiss M. 1964. Am. J. Pathol. 44:269–8757. Kidd M. 1963. Nature 197:192–9358. Terry RD, Katzman R. 1983. Ann. Neurol. 14:497–50659. Katzman R. 1986. N. Engl. J. Med. 314:964–7360. Davies P, Maloney AJ. 1976. Lancet 2:140361. Hyman BT, Van Horsen GW, Damasio AR, Barnes CL. 1984. Science 225:1168–7062. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. 1982. Science

215:1237–3963. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, et al. 1991. Ann. Neurol.

30:572–8064. Glenner GG, Wong CW. 1984. Biochem. Biophys. Res. Commun. 120:885–90


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

65. Haass C. 2004. EMBO J. 23:483–8866. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. 1987. Science

235:877–8067. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, et al. 1987. Nature

325:733–3668. Deleted in proof69. Murrell J, Farlow M, Ghetti B, Benson MD. 1991. Science 254:97–9970. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, et al. 1992. Nature 360:672–

7471. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, et al. 1995. Nature

375:754–6072. Selkoe D, Kopan R. 2003. Annu. Rev. Neurosci. 26:565–9773. Kojro E, Fahrenholz F. 2005. Subcell. Biochem. 38:105–2774. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. 1986. Proc.

Natl. Acad. Sci. USA 83:4913–1775. Hardy JA, Higgins GA. 1992. Science 256:184–8576. Jarrett JT, Lansbury PT Jr. 1993. Cell 73:1055–5877. Hardy J, Selkoe DJ. 2002. Science 297:353–5678. Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS. 1981. Ann. Neurol. 10:184–

9279. Armstrong RA, Myers D, Smith CU. 1993. Dementia 4:16–2080. Thal DR, Rub U, Orantes M, Braak H. 2002. Neurology 58:1791–80081. Braak H, Braak E. 1991. Acta Neuropathol. 82:239–5982. Mackenzie IR, McLachlan RS, Kubu CS, Miller LA. 1996. Neurology 46:425–2983. Siman R, Salidas S. 2004. Neuroscience 129:615–2884. Capell A, Meyn L, Fluhrer R, Teplow DB, Walter J, Haass C. 2002. J. Biol. Chem.

277:5637–4385. Beher D, Elle C, Underwood J, Davis JB, Ward R, et al. 1999. J. Neurochem. 72:1564–7386. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, et al. 1995. Neuron 14:467–7587. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, et al. 1990. Proc. Natl. Acad.

Sci. USA 87:1561–6588. Kaether C, Skehel P, Dotti CG. 2000. Mol. Biol. Cell 11:1213–2489. Amaratunga A, Leeman SE, Kosik KS, Fine RE. 1995. J. Neurochem. 64:2374–7690. Gunawardena S, Goldstein LS. 2001. Neuron 32:389–40191. Jensen PH, Li JY, Dahlstrom A, Dotti CG. 1999. Eur. J. Neurosci. 11:3369–7692. Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. 2001. Nature

414:643–4893. Papp H, Pakaski M, Kasa P. 2002. Neurochem. Int. 41:429–3594. Kasa P, Papp H, Pakaski M. 2001. Brain Res. 909:159–6995. Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M. 1998. J. Biol. Chem. 273:26292–

9496. Lazarov O, Morfini GA, Lee EB, Farah MH, Szodorai A, et al. 2005. J. Neurosci. 25:2386–

9597. Gu Y, Sanjo N, Chen F, Hasegawa H, Petit A, et al. 2004. J. Biol. Chem. 279:31329–3698. Hook VY, Toneff T, Aaron W, Yasothornsrikul S, Bundey R, Reisine T. 2002. J. Neu-

rochem. 81:237–5699. Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH. 2004. Am. J.

Pathol. 165:357–71


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

100. Yang J, Li T. 2005. Exp. Cell Res. 309:379–89101. Inomata H, Nakamura Y, Hayakawa A, Takata H, Suzuki T, et al. 2003. J. Biol. Chem.

278:22946–55102. Matsuda S, Matsuda Y, D’Adamio L. 2003. J. Biol. Chem. 278:38601–6103. Satpute-Krishnan P, DeGiorgis JA, Bearer EL. 2003. Aging Cell 2:305–18104. Zheng P, Eastman J, Vande Pol S, Pimplikar SW. 1998. Proc. Natl. Acad. Sci. USA

95:14745–50105. Muresan Z, Muresan V. 2005. J. Neurosci. 25:3741–51106. Masliah E, Mallory M, Ge N, Saitoh T. 1992. Brain Res. 593:323–28107. Moya KL, Benowitz LI, Schneider GE, Allinquant B. 1994. Dev. Biol. 161:597–603108. Perez RG, Zheng H, Van der Ploeg LH, Koo EH. 1997. J. Neurosci. 17:9407–14109. Allinquant B, Hantraye P, Mailleux P, Moya K, Bouillot C, Prochiantz A. 1995. J. Cell.

Biol. 128:919–27110. Wang ZF, Wang JZ. 2004. Chin. Med. J. 117:775–78111. Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. 1995. J. Neurosci. 15:2157–67112. Muller U, Cristina N, Li ZW, Wolfer DP, Lipp HP, et al. 1994. Cell 79:755–65113. Magara F, Muller U, Li ZW, Lipp HP, Weissmann C, et al. 1999. Proc. Natl. Acad. Sci.

USA 96:4656–61114. Gonzalez-Lima F, Berndt JD, Valla JE, Games D, Reiman EM. 2001. Neuroreport

12:2375–79115. Redwine JM, Kosofsky B, Jacobs RE, Games D, Reilly JF, et al. 2003. Proc. Natl. Acad.

Sci. USA 100:1381–86116. Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA. 2005. EMBO J.

24:2944–55117. Cottrell BA, Galvan V, Banwait S, Gorostiza O, Lombardo CR, et al. 2005. Ann. Neurol.

58:277–89118. Torroja L, Chu H, Kotovsky I, White K. 1999. Curr. Biol. 9:489–92119. Hurd DD, Saxton WM. 1996. Genetics 144:1075–85120. Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, et al. 2001. Proc. Natl.

Acad. Sci. USA 98:10439–44121. Yang G, Gong YD, Gong K, Jiang WL, Kwon E, et al. 2005. Neurosci. Lett. 384:66–71122. Wang P, Yang G, Mosier DR, Chang P, Zaidi T, et al. 2005. J. Neurosci. 25:1219–25123. Torroja L, Packard M, Gorczyca M, White K, Budnik V. 1999. J. Neurosci. 19:7793–803124. Furukawa K, Guo Q, Schellenberg GD, Mattson MP. 1998. J. Neurosci. Res. 52:618–24125. Dowjat WK, Wisniewski T, Efthimiopoulos S, Wisniewski HM. 1999. Neurosci. Lett.

267:141–44126. Pigino G, Pelsman A, Mori H, Busciglio J. 2001. J. Neurosci. 21:834–42127. Figueroa DJ, Morris JA, Ma L, Kandpal G, Chen E, et al. 2002. Neurobiol. Dis. 9:49–60128. Levesque L, Annaert W, Craessaerts K, Mathews PM, Seeger M, et al. 1999. Mol. Med.

5:542–54129. Dowjat WK, Wisniewski H, Wisniewski T. 2001. Neuroscience 103:1–8130. Johnsingh AA, Johnston JM, Merz G, Xu J, Kotula L, et al. 2000. FEBS Lett. 465:53–58131. Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J. 2003. J. Neurosci.

23:4499–508132. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST. 2002. EMBO J. 21:281–93133. Cai D, Leem JY, Greenfield JP, Wang P, Kim BS, et al. 2003. J. Biol. Chem. 278:3446–54134. Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, et al. 2005. J. Neurosci. 25:6755–

64


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

135. Thinakaran G, Regard JB, Bouton CM, Harris CL, Price DL, et al. 1998. Neurobiol. Dis.4:438–53

136. Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ. 1997. Proc. Natl. Acad. Sci. USA 94:8208–13137. Waragai M, Imafuku I, Takeuchi S, Kanazawa I, Oyama F, et al. 1997. Biochem. Biophys.

Res. Commun. 239:480–82138. Verdile G, Martins RN, Duthie M, Holmes E, St George-Hyslop PH, Fraser PE. 2000.

J. Biol. Chem. 275:20794–98139. Pitsi D, Kienlen-Campard P, Octave JN. 2002. J. Neurochem. 83:390–99140. Rockenstein E, Mante M, Alford M, Adame A, Crews L, et al. 2005. J. Biol. Chem.

280:32957–67141. Lee EB, Zhang B, Liu K, Greenbaum EA, Doms RW, et al. 2005. J. Cell. Biol. 168:291–

302142. Caceres A, Potrebic S, Kosik KS. 1991. J. Neurosci. 11:1515–23143. Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH. 1988. Am. J. Pathol. 132:86–

101144. Masliah E, Mallory M, Deerinck T, DeTeresa R, Lamont S, et al. 1993. J. Neuropathol.

Exp. Neurol. 52:619–32145. Yasuhara O, Kawamata T, Aimi Y, McGeer EG, McGeer PL. 1994. Neurosci. Lett. 171:73–

76146. Minamide LS, Striegl AM, Boyle JA, Meberg PJ, Bamburg JR. 2000. Nat. Cell Biol.

2:628–36147. Kowall NW, Kosik KS. 1987. Ann. Neurol. 22:639–43148. Munoz DG, Wang D. 1992. Am. J. Pathol. 140:1167–78149. Booze RM, Mactutus CF, Gutman CR, Davis JN. 1993. J. Neurol. Sci. 119:110–18150. Geula C, Mesulam MM. 1996. Cereb. Cortex 6:165–77151. Davies DC, Brooks JW, Lewis DA. 1993. Neurobiol. Aging 14:353–57152. Sadun AA, Bassi CJ. 1990. Ophthalmology 97:9–17153. Syed AB, Armstrong RA, Smith CU. 2005. Folia Neuropathol. 43:1–6154. Meyerhoff DJ, MacKay S, Constans JM, Norman D, Van Dyke C, et al. 1994. Ann.

Neurol. 36:40–47155. Stahl R, Dietrich O, Teipel S, Hampel H, Reiser MF, Schoenberg SO. 2003. Radiologe

43:566–75156. Lakmache Y, Lassonde M, Gauthier S, Frigon JY, Lepore F. 1998. Proc. Natl. Acad. Sci.

USA 95:9042–46157. Boutajangout A, Authelet M, Blanchard V, Touchet N, Tremp G, et al. 2004. Neurobiol.

Dis. 15:47–60158. Spittaels K, Van den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, et al. 1999.

Am. J. Pathol. 155:2153–65159. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. 1996. J. Neurosci. 16:5795–

811160. Cras P, Kawai M, Lowery D, Gonzalez-DeWhitt P, Greenberg B, Perry G. 1991. Proc.

Natl. Acad. Sci. USA 88:7552–56161. Sennvik K, Bogdanovic N, Volkmann I, Fastbom J, Benedikz E. 2004. J. Cell Mol. Med.

8:127–34162. Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, et al. 2004. J. Neurosci. 24:3592–

99163. Dessi F, Colle MA, Hauw JJ, Duyckaerts C. 1997. Neuroreport 8:3685–89164. Nakamura Y, Takeda M, Yoshimi K, Hattori H, Hariguchi S, et al. 1994. Acta Neuropathol.

87:23–31


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

ANRV277-BI75-23 ARI 3 May 2006 10:43

165. Burke WJ, Park DH, Chung HD, Marshall GL, Haring JH, Joh TH. 1990. Brain Res.537:83–87

166. Mann DM, Sumpter PQ, Davies CA, Yates PO. 1987. Acta Neuropathol. 73:181–84167. Richard S, Brion JP, Couck AM, Flament-Durand J. 1989. J. Submicrosc. Cytol. Pathol.

21:461–67168. Price DL, Altschuler RJ, Struble RG, Casanova MF, Cork LC, Murphy DB. 1986. Brain

Res. 385:305–10169. Praprotnik D, Smith MA, Richey PL, Vinters HV, Perry G. 1996. Acta Neuropathol.

91:226–35170. Pike CJ, Cummings BJ, Cotman CW. 1992. Neuroreport 3:769–72171. Hiruma H, Katakura T, Takahashi S, Ichikawa T, Kawakami T. 2003. J. Neurosci.

23:8967–77172. Kasa P, Papp H, Kovacs I, Forgon M, Penke B, Yamaguchi H. 2000. Neurosci. Lett.

278:117–19173. Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. 2002. J. Cell. Biol. 156:1051–

63174. Trojanowski JQ, Smith AB, Huryn D, Lee VM. 2005. Expert Opin. Pharmacother. 6:683–

86175. Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, et al. 2005. Proc. Natl. Acad.

Sci. USA 102:227–31176. Aston-Jones G, Rogers J, Shaver RD, Dinan TG, Moss DE. 1985. Nature 318:462–64177. Nierenberg J, Pomara N, Hoptman MJ, Sidtis JJ, Ardekani BA, Lim KO. 2005. Neurore-

port 16:1369–72178. Mufson EJ, Kordower JH. 1992. Proc. Natl. Acad. Sci. USA 89:569–73179. Mufson EJ, Conner JM, Kordower JH. 1995. Neuroreport 6:1063–66180. Geula C, Mesulam MM. 1989. Neuroscience 33:469–81181. Dai J, Buijs RM, Kamphorst W, Swaab DF. 2002. Brain Res. 948:138–44182. Roediger B, Armati PJ. 2003. Neurobiol. Dis. 13:222–29183. Carson C, Saleh M, Fung FW, Nicholson DW, Roskams AJ. 2005. J. Neurosci. 25:6092–

104184. Delcroix JD, Valletta J, Wu C, Howe CL, Lai CF, et al. 2004. Prog. Brain Res. 146:3–23185. Dhaenens CM, Van Brussel E, Schraen-Maschke S, Pasquier F, Delacourte A, Sablon-

niere B. 2004. Neurosci. Lett. 368:290–92


Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

Contents ARI 22 April 2006 9:16

Annual Reviewof Biochemistry

Volume 75, 2006Contents

Wanderings of a DNA Enzymologist: From DNA Polymerase to ViralLatencyI. Robert Lehman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Signaling Pathways in Skeletal Muscle RemodelingRhonda Bassel-Duby and Eric N. Olson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �19

Biosynthesis and Assembly of Capsular Polysaccharides inEscherichia coliChris Whitfield � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �39

Energy Converting NADH:Quinone Oxidoreductase (Complex I)Ulrich Brandt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �69

Tyrphostins and Other Tyrosine Kinase InhibitorsAlexander Levitzki and Eyal Mishani � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �93

Break-Induced Replication and Recombinational Telomere Elongationin YeastMichael J. McEachern and James E. Haber � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 111

LKB1-Dependent Signaling PathwaysDario R. Alessi, Kei Sakamoto, and Jose R. Bayascas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 137

Energy Transduction: Proton Transfer Through the RespiratoryComplexesJonathan P. Hosler, Shelagh Ferguson-Miller, and Denise A. Mills � � � � � � � � � � � � � � � � � � � � � � 165

The Death-Associated Protein Kinases: Structure, Function, andBeyondShani Bialik and Adi Kimchi � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 189

Mechanisms for Chromosome and Plasmid SegregationSantanu Kumar Ghosh, Sujata Hajra, Andrew Paek,

and Makkuni Jayaram � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 211

Chromatin Modifications by Methylation and Ubiquitination:Implications in the Regulation of Gene ExpressionAli Shilatifard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 243

v

Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.


Structure and Mechanism of the Hsp90 Molecular ChaperoneMachineryLaurence H. Pearl and Chrisostomos Prodromou � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 271

Biochemistry of Mammalian Peroxisomes RevisitedRonald J.A. Wanders and Hans R. Waterham � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 295

Protein Misfolding, Functional Amyloid, and Human DiseaseFabrizio Chiti and Christopher M. Dobson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 333

Obesity-Related Derangements in Metabolic RegulationDeborah M. Muoio and Christopher B. Newgard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 367

Cold-Adapted EnzymesKhawar Sohail Siddiqui and Ricardo Cavicchioli � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 403

The Biochemistry of SirtuinsAnthony A. Sauve, Cynthia Wolberger, Vern L. Schramm, and Jef D. Boeke � � � � � � � � � � � 435

Dynamic Filaments of the Bacterial CytoskeletonKatharine A. Michie and Jan Lowe � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 467

The Structure and Function of Telomerase Reverse TranscriptaseChantal Autexier and Neal F. Lue � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 493

Relating Protein Motion to CatalysisSharon Hammes-Schiffer and Stephen J. Benkovic � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 519

Animal Cytokinesis: From Parts List to MechanismsUlrike S. Eggert, Timothy J. Mitchison, and Christine M. Field � � � � � � � � � � � � � � � � � � � � � � � � 543

Mechanisms of Site-Specific RecombinationNigel D.F. Grindley, Katrine L. Whiteson, and Phoebe A. Rice � � � � � � � � � � � � � � � � � � � � � � � � � � 567

Axonal Transport and Alzheimer’s DiseaseGorazd B. Stokin and Lawrence S.B. Goldstein � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 607

Asparagine Synthetase ChemotherapyNigel G.J. Richards and Michael S. Kilberg � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 629

Domains, Motifs, and Scaffolds: The Role of Modular Interactions inthe Evolution and Wiring of Cell Signaling CircuitsRoby P. Bhattacharyya, Attila Remenyi, Brian J. Yeh, and Wendell A. Lim � � � � � � � � � � � � � 655

Ribonucleotide ReductasesPar Nordlund and Peter Reichard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 681

Introduction to the Membrane Protein Reviews: The Interplay ofStructure, Dynamics, and Environment in Membrane ProteinFunctionJonathan N. Sachs and Donald M. Engelman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 707

vi Contents

Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.


Relations Between Structure and Function of the MitochondrialADP/ATP CarrierH. Nury, C. Dahout-Gonzalez, V. Trezeguet, G.J.M. Lauquin,G. Brandolin, and E. Pebay-Peyroula � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 713

G Protein–Coupled Receptor RhodopsinKrzysztof Palczewski � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 743

Transmembrane Traffic in the Cytochrome b6 f ComplexWilliam A. Cramer, Huamin Zhang, Jiusheng Yan, Genji Kurisu,

and Janet L. Smith � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 769

INDEXES

Subject Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 791

Author Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 825

ERRATA

An online log of corrections to Annual Review of Biochemistry chapters (if any, 1977 tothe present) may be found at http://biochem.annualreviews.org/errata.shtml

Contents vii

Ann

u. R

ev. B

ioch

em. 2

006.

75:6

07-6

27. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by U

nive

rsity

of

Tex

as L

ibra

ries

on

01/0

9/08

. For

per

sona

l use

onl

y.

axonal transport and alzheimer's disease ...lafer/2008/stokin-goldstein06.pdfjor motor protein...

Documents