title: Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation.
abstract: In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-β (Aβ) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aβ generation by directly associating with β-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aβ production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases β-amyloid plaques and soluble Aβ. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aβ-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Neuroscience, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
authors.forename: Demian
authors.initials: D
authors.lastname: Obregon
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Juan
authors.initials: J
authors.lastname: Deng
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.forename: Donna
authors.initials: D
authors.lastname: Darlington
authors.forename: Md
authors.initials: M
authors.lastname: Shahaduzzaman
authors.forename: Yuyuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human