Alzheimer's Disease Signaling

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 amyloid precursor protein (APP). APP is an integral membrane protein that undergoes proteolytic processing. APP is initially cleaved by α-secretase to generate sAPPα and a C83 carboxy-terminal fragment. The presence of sAPPα is associated with normal synaptic signaling and regulates processes like neuronal survival and synaptic plasticity that contribute to higher order brain functions like learning and memory, and other behaviors. Alternatively, APP may be cleaved sequentially by β-secretase and γ-secretase to release extracellular monomers of varying sizes, the most significant of which is Aβ40/42. In the disease state, an imbalance among APP processing pathways leads to increased aggregation of neurotoxic monomers, yielding Aβ oligomerization and plaque formation. Pathogenic Aβ aggregation results in blocked ion channels, disruption of calcium homeostasis, mitochondrial oxidative stress, impaired energy metabolism and abnormal glucose regulation, altered synaptic function, and ultimately, neuronal cell death. A number of glial cell types, including astrocytes and microglia, have been implicated as both neuroprotective and pathogenic in the context of amyloid monomer, oligomer, and plaque accumulation. Alzheimer’s disease is also characterized by the presence of neurofibrillary tangles, which are composed of hyperphosphorylated forms of the microtubule-associated protein Tau. GSK-3α/β 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, followed by microtubule destabilization and oligomerization of Tau protein, ultimately leading to neurofibrillary tangles within the cell. Progressive accumulation of these tangles leads to apoptosis of the neuron.

Selected Reviews:

• Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat. Med. 10 Suppl, S2–9.

• Chen JX, Yan SS (2010) Role of mitochondrial amyloid-beta in Alzheimer's disease. J. Alzheimers Dis. 20 Suppl 2, S569–78.

• Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P (2012) Alzheimer culprits: cellular crossroads and interplay. Cell. Signal. 24(9), 1831–40.

• Marcus JN, Schachter J (2011) Targeting post-translational modifications on tau as a therapeutic strategy for Alzheimer's disease. J. Neurogenet. 25(4), 127–33.

• Müller WE, Eckert A, Kurz C, Eckert GP, Leuner K (2010) Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease--therapeutic aspects. Mol. Neurobiol. 41(2-3), 159–71.

• Nizzari M, Thellung S, Corsaro A, Villa V, Pagano A, Porcile C, Russo C, Florio T (2012) Neurodegeneration in Alzheimer disease: role of amyloid precursor protein and presenilin 1 intracellular signaling. J Toxicol 2012, 187297.

• Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283(44), 29615–9.

• Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020). Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Molecular Neurodegeneration 15.

• Lane, C. A., Hardy, J., & Schott, J. M. (2018). Alzheimer’s disease. European Journal of Neurology 25(1), 59–70.

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 June 2022