Soluble amyloid precursor protein-[alpha] modulates [beta]-secretase activity and amyloid-[beta] generation

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 proce...

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Published in:Nature communications 2012-04, Vol.3, p.777
Main Authors: Obregon, Demian, Hou, Huayan, Deng, Juan, Giunta, Brian, Tian, Jun, Darlington, Donna, Shahaduzzaman, Md, Zhu, Yuyuan, Mori, Takashi, Mattson, Mark P, Tan, Jun
Format: Article
Language:English
Subjects:
Alzheimer's disease
Brain
Enzymes
Metabolism
Metabolites
Mutation
Neurosciences
Oxidative stress
Pathology
Peptides
Proteins
Risk factors
Transgenic animals
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container_title Nature communications
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creator Obregon, Demian
Hou, Huayan
Deng, Juan
Giunta, Brian
Tian, Jun
Darlington, Donna
Shahaduzzaman, Md
Zhu, Yuyuan
Mori, Takashi
Mattson, Mark P
Tan, Jun
description 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.
doi_str_mv 10.1038/ncomms1781
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subjects Alzheimer's disease
Brain
Enzymes
Metabolism
Metabolites
Mutation
Neurosciences
Oxidative stress
Pathology
Peptides
Proteins
Risk factors
Transgenic animals
title Soluble amyloid precursor protein-[alpha] modulates [beta]-secretase activity and amyloid-[beta] generation
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