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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]

PMID: 22491325

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Project description:INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering A? production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP ?-site cleavage (equivalent to A?40), and Notch ?-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A? production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A? was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A? reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A? production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A? in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A? was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Dataset Information

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

Publications

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

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