2. Academic Validation
  3. Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4

Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4

  • Neuron. 2023 Apr 4;S0896-6273(23)00220-9. doi: 10.1016/j.neuron.2023.03.024.
Xianglong Hou 1,  Xuexin Zhang 1,  Huan Zou 1,  Mingfeng Guan 1,  Chaoying Fu 2,  Wenyuan Wang 2,  Zai-Rong Zhang 2,  Yang Geng 3,  Yelin Chen 4
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China. Electronic address: gengyang@sioc.ac.cn.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China. Electronic address: chenyelin@sioc.ac.cn.
PMID: 37040764 DOI: 10.1016/j.neuron.2023.03.024
Abstract

Aberrant low γ-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer's disease (fAD). However, the role of γ-secretase in the more prevalent sporadic AD (sAD) remains unaddressed. Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor of sAD, interacts with γ-secretase and inhibits it with substrate specificity in cell-autonomous manners through its conserved C-terminal region (CT). This ApoE CT-mediated inhibitory activity is differentially compromised in different ApoE isoforms, resulting in an ApoE2 > ApoE3 > ApoE4 potency rank order inversely correlating to their associated AD risk. Interestingly, in an AD mouse model, neuronal ApoE CT migrates to amyloid plaques in the subiculum from other regions and alleviates the plaque burden. Together, our data reveal a hidden role of ApoE as a γ-secretase Inhibitor with substrate specificity and suggest that this precision γ-inhibition by ApoE may protect against the risk of sAD.

Keywords

Alzheimer’s disease; amyloid precursor protein; amyloid β; apolipoprotein E; γ-secretase.

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