| First Author | Hou X | Year | 2023 |
| Journal | Neuron | PubMed ID | 37040764 |
| Mgi Jnum | J:335540 | Mgi Id | MGI:7470623 |
| Doi | 10.1016/j.neuron.2023.03.024 | Citation | Hou X, et al. (2023) Differential and substrate-specific inhibition of gamma-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron |
| abstractText | Aberrant low gamma-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer's disease (fAD). However, the role of gamma-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 gamma-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 gamma-secretase inhibitor with substrate specificity and suggest that this precision gamma-inhibition by ApoE may protect against the risk of sAD. |
