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Pathway Description:

Alzheimer’s disease is one of the most common neurodegenerative diseases worldwide. Clinically, it is characterized by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles, resulting in neuronal dysfunction and cell death. Central to this disease is the differential processing of the integral membrane protein APP (Amyloid Precursor Protein) in the normal versus disease state. In the normal state, APP is initially cleaved by α-secretase to generate sAPPα and a C83 carboxyterminal fragment. The presence of sAPPα is associated with normal synaptic signaling and results in synaptic plasticity, learning and memory, emotional behaviors, and neuronal survival. In the disease state, APP is cleaved sequentially by β-secretase and γ-secretase to release an extracellular fragment called Aβ40/42. This neurotoxic fragment frequently aggregates and results in Aβ40/42 oligomerization and plaque formation. Aβ40/42 aggregation results in blocked ion channels, disruption of calcium homeostasis, mitochondrial oxidative stress, impaired energy metabolism and abnormal glucose regulation, and ultimately neuronal cell death. Alzheimer’s disease is also characterized by the presence of neurofibrillary tangles. These tangles are the result of hyperphosphorylation of the microtubule-associated protein Tau. GSK-3β and CDK5 are the kinases primarily responsible for phosphorylation of Tau, although other kinases such as PKC, PKA, and ERK2 are also involved. Hyperphosphorylation of Tau results in the dissociation of Tau from the microtubule, leading to microtubule destabilization and oligomerization of the Tau protein within the cell. Neurofibrillary tangles form as a result of Tau oligomerization and lead to apoptosis of the neuron.

Selected Reviews:

We would like to thank Prof. Christopher Phiel, University of Colorado-Denver, and Prof. Jeff Kuret, The Ohio State University, Columbus, OH for contributing to this diagram.

created July 2009

revised September 2012