Year: 2010
Type: review
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddq160
Authors: L. Crews, E. Masliah
Institution: University of California San Diego
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2135957529