GABAergic signaling abnormalities in a novel CLU mutation Alzheimer's disease mouse model.

The CLU rs11136000C mutation (CLU) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLU leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLU AD. Examination of grafted CLU medial ganglionic eminence progenitors (CLU hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLU hiMGEs also impaired cognition in chimeric mice and caused AD-related pathologies. The expression of GABA A receptor, subunit alpha 2 (Gabrα2) 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 AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.