p35

Akt CDK5

Calpain

GSK-3α/βTau

AICDAICD

APP

Casp-3,-9

APP

NMDARNMDAR

sAPPβsAPPα Aβ40/42

AMPARAMPAR AcetylcholineReceptors:

nAChRmAChR

GlucoseTransporters

GlucoseTransporters

DR6

N-APP

Apoptosis

Apoptosis

Apoptosis DestabilizedMicrotubules

Hyperphosphorylation of Tau

Activation of PKC, PKA, Erk2

Casp-6

Membrane Damage

Oxidative Stress

ROS Formation

MicrogliaActivation

Inflammatory Cytokines

Lipid Peroxidation

Amyloid Plaques Aβ Misfolding, Aggregation

ROS Formation

p53, Bad,Bax productionand activation

Normal State Alzheimer’s Disease State

Neurofibrillary Tangles

β-SecretaseAPP

APPIntracellular

Domain

PEN-2Aph

NicastrinPresenilin

Nuclear translocationTranscriptional regulation

Normal Axon

Pruning

Aberrant Neuronal Death

Increased Neuronal Survival,Neutrite Outgrowth,

Synaptic sAPPα Plasticity,Cell Adhesion

α-Secretase

γ-Secretase

γ-Secretase

p25

Ca2+Na+Glc

nAChRmAChR

© 2009 – 2010 Cell Signaling Technology, Inc. Amyloid Plaque and Neurofibrillary Tangle Formation in Alzheimer’s Disease • created July 2009 • revised November 2010

Amyloid Plaque and Neurofibrillary Tangle Formation in Alzheimer’s Disease

www.cellsignal.com

Direct Stimulatory ModificationKinase

Phosphatase

Caspase

Receptor

Cyclin, pro-apoptotic

Enzyme

pro-survival

GAP / GEF

GTPase

G-protein, ribosomal subunit

Transcription Factor

Transcriptional Stimulation

Transcriptional Inhibition

Translocation

Separation of Subunits or Cleavage Products

Joining of Subunits

Direct Inhibitory Modification

Multistep Stimulatory Modification

Multistep Inhibitory Modification

Tentative Stimulatory Modification

Tentative Inhibitory Modification

Signaling Pathways Key

www.cellsignal.com

© 2003 - 2010 Cell Signaling Technology, Inc.

Acetylase

Deacetylase