Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta) peptides forming senile plaques (SP) and the intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.
Highlights
Alzheimer’s disease (AD) was originally described by Alois Alzheimer in 1906 and was renamed several years later by Emil Kraepelin [1]
This review focuses on the new developments of amyloid cascade hypothesis and its relevance to the most recent research advances in the genetics, neuropathology and pathogenesis of AD
Neprilysin/insulin-degrading enzyme While familial early-onset AD is associated with increased Aβ production, defective Aβ degradation may be involved in late-onset AD (LOAD), which constitutes approximately 90% of all AD cases [81]
Summary
Alzheimer’s disease (AD) was originally described by Alois Alzheimer in 1906 and was renamed several years later by Emil Kraepelin [1]. It is recently demonstrated that increased expression of ApoE by the retinoid X receptors agonist results in enhanced clearance of soluble Aβ and reduced Aβ plaque, and leads to reversal of cognitive deficits and improvement of synaptic functions in an AD mouse model [72]. In contrast to the observations mentioned above, Lesne et al identified the extracellular accumulation of a soluble 56-kDa Aβ assembly (termed Aβ*56) composed of 12 Aβ peptides that contributes to the memory impairment in Tg2576 mice [139] This finding has been supported by others using transgenic mice with increased formation of amyloid plaques but reduced Aβ*56 levels [140]. Accumulating evidence suggests that functional loss of TGF-β signaling may contribute to Aβ-induced neurodegeneration and tau pathology, indicating a neuroprotective role of this pathway [151]
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