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Targeting the ?-/?-secretase interaction reduces ?-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.

ABSTRACT: Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of ?-secretase or ?-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and ?-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress A? generation. Through high-throughput screening, we discovered that 3-?-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces A? production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce A? production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and A?-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics.

SUBMITTER: Cui J 

PROVIDER: S-EPMC4860824 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.

Cui Jin J   Wang Xiaoyin X   Li Xiaohang X   Wang Xin X   Zhang Chenlu C   Li Wei W   Zhang Yangming Y   Gu Haifeng H   Xie Xin X   Nan Fajun F   Zhao Jian J   Pei Gang G  

Cell discovery 20150818

Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of γ-secretase or β-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and γ-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress Aβ generation. Through high-throughput screening, we discovered that 3-α-akebonoic acid (3A  ...[more]