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Abstract
Alzhelmer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing β amylold (Aβ) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of familial or sporadic AD have not been fully elucidated. About 10% of all cases of AD occur as autosomal dominant inherited forms of early-onset AD, which are caused by mutations in the genes encoding APP, presenilin-1 and presenilin-2. Proteolytic processing of APP by β-γ-secretase and caspase generates Aβ and carboxyl-terminal fragments of APP (APP-CTFs), which have been implicated in the pathogenesis of AD. The presenilins function as one of the γ-secretases. Aβ which is the main component of the amyloid plaques found, is known to exert neurotoxicity by accumulating free radicals, disturbing calcium homeostasis, evoking inflammatory response and activating signaling pathways. The CTFs have been found in AD patients' brain and reported to exhibit much greater neurotoxicity than Aβ. Furthermore CTFs are known to impair calcium homeostasis and learning and memory, triggering a strong inflammatory reaction through MAPKs- and NF-κB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus and in turn, affected transcription of genes including glycogen synthase kinase-3β which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. One of the hallmarks of AD, neurofibrillary tangles (NFT), is formed by insoluble intracellular polymers of hyperphosphorylated tau that is believed to cause apoptosis by disrupting cytoskeletal and axonal transport. This review covers the processing of APP, toxic mechanisms of Aβ and CTFs of APP, presenilin and also tau in relation to the pathogenesis of AD.
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