| First Author | Chen C | Year | 2023 |
| Journal | Transl Res | Volume | 260 |
| Pages | 32-45 | PubMed ID | 37211336 |
| Mgi Jnum | J:351759 | Mgi Id | MGI:7663220 |
| Doi | 10.1016/j.trsl.2023.05.003 | Citation | Chen C, et al. (2023) GABAergic signaling abnormalities in a novel CLU mutation Alzheimer's disease mouse model. Transl Res 260:32-45 |
| abstractText | The CLU rs11136000C mutation (CLU(C)) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLU(C) leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLU(C) AD. Examination of grafted CLU(C) medial ganglionic eminence progenitors (CLU(C) hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLU(C) hiMGEs also impaired cognition in chimeric mice and caused AD-related pathologies. The expression of GABA A receptor, subunit alpha 2 (Gabralpha2) was higher in chimeric mice. Interestingly, cognitive impairment in chimeric mice was reversed by treatment with pentylenetetrazole, which is a GABA A receptor inhibitor. Taken together, these findings shed light on the pathogenesis of CLU(C) AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder. |
