Molecular mechanisms of neurodegeneration in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by cognitive impairment, progressive neurodegeneration and formation of amyloid-beta (Abeta)-containing plaques and neurofibrillary tangles composed of hyperphosphorylated tau. The neurodegenerative process in AD is initially characterized by synaptic damage accompanied by neuronal loss. In addition, recent evidence suggests that alterations in adult neurogenesis in the hippocampus might play a role. Synaptic loss is one of the strongest correlates to the cognitive impairment in patients with AD. Several lines of investigation support the notion that the synaptic pathology and defective neurogenesis in AD are related to progressive accumulation of Abeta oligomers rather than fibrils. Abnormal accumulation of Abeta resulting in the formation of toxic oligomers is the result of an imbalance between the levels of Abeta production, aggregation and clearance. Abeta oligomers might lead to synaptic damage by forming pore-like structures with channel activity; alterations in glutamate receptors; circuitry hyper-excitability; mitochondrial dysfunction; lysosomal failure and alterations in signaling pathways related to synaptic plasticity, neuronal cell and neurogenesis. A number of signaling proteins, including fyn kinase; glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase-5 (CDK5), are involved in the neurodegenerative progression of AD. Therapies for AD might require the development of anti-aggregation compounds, pro-clearance pathways and blockers of hyperactive signaling pathways.

Figure 1.

Mechanisms of neurodegeneration in AD. Defective cellular processes can lead to the accumulation of Aβ dimers, trimers and oligomers, which in turn contribute to neurogenesis defects and synaptic damage.

Figure 2.

APP metabolism, Aβ oligomerization and signaling involvement in the mechanisms of synaptic damage in AD. Proteolytic cleavage of APP by β- and γ-secretase results in the generation of the Aβ_1–42 monomer, which under pathological conditions can assemble into potentially toxic oligomers. Enzymes such as Neprilysin and insulin-degrading enzyme (IDE) can degrade the Aβ monomer, whereas oligomers can be sequestered into fibrillar aggregates in plaques. Oligomers may be the toxic Aβ species that contribute to de-regulation of signaling pathways (Fyn, FAK, GSK3β, CDK5) and result in alterations to cytoskeletal and synaptic proteins and subsequent synaptic and neuronal damage. Aβ accumulation is mediated by factors including rates of peptide production, aggregation and clearance.

Figure 3.

Aberrant activation of signaling molecules such as CDK5 (CDK5^act) might impair adult neurogenesis during the cell maturation stage. (A) Schematic model of the stages that comprise the neurogenic process of NPC development in the adult brain, and representative markers that can be utilized to identify cells in various phases of development. (B) Aberrant signaling through CDK5 and other pathways might disrupt the maturation stage of adult neurogenesis in the pathogenesis of AD.