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

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

Cell discovery (2015-01-01)
Jin Cui, Xiaoyin Wang, Xiaohang Li, Xin Wang, Chenlu Zhang, Wei Li, Yangming Zhang, Haifeng Gu, Xin Xie, Fajun Nan, Jian Zhao, Gang Pei
摘要

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 (3AA) interferes with PS1/BACE1 interaction and reduces Aβ 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 Aβ production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and Aβ-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics.

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