title: The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease.
abstract: The amyloid-beta (Aβ) peptide is the derivative of amyloid precursor protein (APP) generated through sequential proteolytic processing by β- and γ-secretases. Excessive accumulation of Aβ, the main constituent of amyloid plaques, has been implicated in the etiology of Alzheimer's disease (AD). It was found recently that the impairments of neurogenesis in brain were associated with the pathogenesis of AD. Furthermore recent findings implicated that APP could function to influence proliferation of neural progenitor cells (NPC) and might regulate transcriptional activity of various genes. Studies demonstrated that influence of neurogenesis by APP is conferred differently via its two separate domains, soluble secreted APPs (sAPPs, mainly sAPPα) and APP intracellular domain (AICD). The sAPPα was shown to be neuroprotective and important to neurogenesis, whereas AICD was found to negatively modulate neurogenesis. Furthermore, it was demonstrated recently that microRNA could function to regulate APP expression, APP processing, Aβ accumulation and subsequently influence neurotoxicity and neurogenesis related to APP, which was implicated to AD pathogenesis, especially for sporadic AD. Based on data accumulated, secretase balances were proposed. These secretase balances could influence the downstream balance related to regulation of neurogenesis by AICD and sAPPα as well as balance related to influence of neuron viability by Aβ and sAPPα. Disruption of these secretase balances could be culprits to AD onset.
authors.affiliation: National Neuroscience Institute; Singapore.
authors.forename: Zhi-dong
authors.initials: ZD
authors.lastname: Zhou
authors.forename: Christine Hui-shan
authors.initials: CH
authors.lastname: Chan
authors.forename: Quan-hong
authors.initials: QH
authors.lastname: Ma
authors.forename: Xiao-hong
authors.initials: XH
authors.lastname: Xu
authors.forename: Zhi-cheng
authors.initials: ZC
authors.lastname: Xiao
authors.forename: Eng-king
authors.initials: EK
authors.lastname: Tan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology; D002465:Cell Movement; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D035683:MicroRNAs; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases