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Soluble amyloid precursor protein-? modulates ?-secretase activity and amyloid-? generation.

ABSTRACT: In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-? (A?) peptides accumulate. Here we show that soluble amyloid precursor protein-? (sAPP-?) decreases A? generation by directly associating with ?-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-? using antibodies enhances A? production; in transgenic mice with AD-like pathology, sAPP-? overexpression decreases ?-amyloid plaques and soluble A?. In support, immunoneutralization of sAPP-? 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-? in brains of AD patients, inadequate sAPP-? levels may be sufficient to polarize APP processing towards the amyloidogenic, A?-producing route. Therefore, restoration of sAPP-? or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.

SUBMITTER: Obregon D 

PROVIDER: S-EPMC3520614 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation.

Obregon Demian D   Hou Huayan H   Deng Juan J   Giunta Brian B   Tian Jun J   Darlington Donna D   Shahaduzzaman Md M   Zhu Yuyuan Y   Mori Takashi T   Mattson Mark P MP   Tan Jun J  

Nature communications 20120410

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  ...[more]

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