Alzheimer's disease

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The content:Structure of the brain

Important proteins in our brain

Alzheimer’s disease

Structure of the brain:

Cerebrum and cerebellum

Cerebrum:

Frontal lobe

Parietal lobe

Temporal lobe

Occipital lobe

>>>>>>>>>>

Brain stem

Frontal brain:

BehaviorAbstract thought processes

Problem solvingAttention

Creative thoughtSome emotion

IntellectReflectionJudgmentInitiativeInhibition

Coordination of movementsGeneralized and mass movements

Some eye movementsSense of smell

Muscle movementsSkilled movementsSome motor skillsPhysical reaction

Parietal lobe

Sense of touch (tactile senstation)

Appreciation of form through touch (stereognosis)

Response to internal stimuli (proprioception)

Sensory combination and comprehension

Some language and reading functions

Some visual functions

Temporal lobe

Auditory memories

Some hearing

Visual memories

Some vision pathways

Other memory

Music

Fear

Some language

Some speech

Some behavior amd emotions

Sense of identity

Occipital lobe

Vision

Reading

Cerebellum:

Balance

Posture

Cardiac, respiratory, and vasomotor centers

The brain stem:

Motor and sensory pathway to body and face

Vital centers: cardiac, respiratory, vasomotor

Neurons in the brain:

Proteins in the brain:tau

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these

proteins are mostly found in neurons compared to non-neuronal cells. One of tau's main functions is to

modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar

functions, as suggested by tau knockout mice, who did not show abnormalities in brain development -possibly because of compensation in tau deficiency

by other MAPs.

Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as

needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of axons which essentially lock down the microtubules and MAP2 that stabilizes

microtubules in dendrites.

Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling

microtubule stability: isoforms and phosphorylation.

Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains

and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively-charged

(allowing it to bind to the negatively-charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in

exons 2, 3, and 10 of the tau gene.

Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been

reported on approximately 30 of these sites in normal tau proteins.Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau,

resulting in disruption of microtubule organization.

Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[8] The degree of phosphorylation in all six isoforms decreases with age due to

the activation of phosphatases.

Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight

filaments, which are involved in the pathogenesis of Alzheimer's disease and other tauopathies.

All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments

from Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of

aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that

contribute to a number of neurodegenerative diseases.

Normal function of APPAmyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation,[3] neural plasticity[4] and iron export.[5] APP is best known as the precursor molecule whose proteolysis generates beta amyloid (Aβ), a 37 to 49 amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

APP is an ancient and highly conserved protein In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240

kilobases.Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 365 to 770 amino acids, with certain isoforms

preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease.[9] Homologous proteins have been identified in other organisms such as Drosophila (fruit

flies), C. elegans (roundworms), and all mammals.The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved

across species and has no obvious connection with APP's native-state biological functions.

Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to

Alzheimer's disease.For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase

production of Aβ.*14]

A mutation (A673T) in the APP gene protects against Alzheimer’s disease. This substitution is adjacent to the beta secretase cleavage site and results in a

40% reduction in the formation of amyloid beta in vitro.

#amyloid protein in the brain

. In Alzheimer’s disease (AD), amyloid fibrils are formed from Aβ peptide. This peptide is produced at cholesterol-rich regions of neuronal membranes and secreted into the extracellular space. Aβ peptide can vary in length. The 40-residue peptide Aβ(1–40) represents the most abundant Aβ species in normal and AD brains, followed by the 42-residue peptide Aβ(1–42). Aβ(1–40) and Aβ(1–42) are able to adopt many differently shaped aggregates including amyloid fibrils as well as nonfibrillar aggregates that are sometimes termed also Aβ “oligomers” .It is not well established which Aβ state is most responsible for AD or why. Nor exists consensus on the precise subcellular location of Aβ pathogenicity. Aβ peptide and Aβ amyloid plaques typically occur outside the cell

Mechanism of amyloid beta:

accumulation of heterogeneous aggregated APP fragments and Abeta appears to mimic the pathophysiologyof dystrophic neurites, where the same spectrum of components has been identified by immunohistochemistry. In the brain, this residue appears to be released into the extracellular space, possibly by a partially apoptotic mechanism that is restricted to the distal compartments of the neuron. Ultimately, this insoluble residue may be further digested to the protease-resistant A(beta)n-42 core, perhaps by microglia, where it accumulates as senile plaques. Thus, the dystrophic neurites are likely to be the source of the immediate precursors of amyloid in the senile plaques. This is the opposite of the commonly held view that extracellular accumulation of amyloid induces dystrophic neurites. Many of the key pathological events of AD may also be directly related to the intracellular accumulation of this insoluble amyloid. The aggregated, intracellular amyloid induces the production of reactive oxygen species (ROS) and lipid peroxidation products and ultimately results in the leakage of the lysosomal membrane. The breakdown of the lysosomal membrane may be a key pathogenic event, leading to the release of heparan sulfate and lysosomal hydrolases into the cytosol.

Result (accumulation of beta amyloid)

AD pathogenesis is believed to be triggered by the accumulation of the amyloid-β peptide (Aβ), which is due to overproduction of Aβ and/or the failure of clearance mechanisms. Aβ self-aggregates into oligomers, which can be of various sizes, and forms diffuse and neuritic plaques in the parenchyma and blood vessels. Aβ oligomers and plaques are potent synaptotoxins, block proteasome function, inhibit mitochondrial activity, alter intracellular Ca2+ levels and stimulate inflammatory processes.

Loss of the normal physiological functions of Aβ is also thought to contribute to neuronal dysfunction. Aβ interacts with the signalling pathways that regulate the phosphorylation of the

microtubule-associated protein tau. Hyperphosphorylation of tau disrupts its normal function in regulating axonal transport

and leads to the accumulation of neurofibrillary tangles and toxic species of soluble tau. Furthermore, degradation of

hyperphosphorylated tau by the proteasome is inhibited by the actions of Aβ. These two proteins and their associated signallingpathways therefore represent important therapeutic targets for

AD.

Genes and beta amyloid Abeta is generated by proteolytic processing of the beta-amyloid precursor protein (betaAPP) involving the combined action of beta- and gamma-secretase. Cleavage within the Abeta domain by alpha-secretaseprevents Abeta generation. In some very rare cases of familial AD (FAD), mutations have been identified within the betaAPP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect betaAPP processing by increasing Abeta production,

References:www.nature.com/nrn/posters/ad/index.hthttp://

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10653281www.ncbi.nlm.nih.gov/pubmed/http://

en.wikipedia.org/wiki/Amyloid_precursor_http://protein

en.wikipedia.org/wiki/Amyloid_precursor_http://protein