Hyperactivity of subicular parvalbumin interneurons drives early amyloid pathology and cognitive deficits in Alzheimerâ€TMs disease by Yan-Bing Chen & Bo Jiang & Kai Zhuang & He Wang & Hui-Min Peng & Bo-Wen Zhong & Wen-Ting Xie & Kai-Wei Chen & Ting-Ting Zou & Ya Wang & Hui-Li Yang & Qingwei Yang & Jiechao Zhou & Li Zhong & Li-Hua Zhang & Jie Zhang instant download

Hyperactivity of subicular parvalbumin interneurons drives early amyloid pathology and cognitive deficits in Alzheimerâ€TMs disease by Yan-Bing Chen & Bo Jiang & Kai Zhuang & He Wang & Hui-Min Peng & Bo-Wen Zhong & Wen-Ting Xie & Kai-Wei Chen & Ting-Ting Zou & Ya Wang & Hui-Li Yang & Qingwei Yang & Jiechao Zhou & Li Zhong & Li-Hua Zhang & Jie Zhang instant download

Atrophy of the subiculum is the earliest hippocampal anatomical marker of Alzheimer’s disease (AD) and is closely associated withearly cognitive decline. However, the underlying mechanisms driving this vulnerability remain unclear. In this study, using the5×FAD mouse model, we identified significant amyloid-beta (Aβ) accumulation in the subiculum during the early stages of AD.Through a combination of laser microdissection and proteomic analysis, we uncovered early dysregulation of GABAergic neurons inthe subiculum. Further investigation revealed that parvalbumin (PV) interneurons (PV-INs) were key drivers of Aβ pathology,1234567890();,:exhibiting pronounced hyperactivity during the initial stages of AD. Targeted inhibition of this PV interneuron hyperactivity at theonset of AD, using chemogenetic approaches and PV downregulation, significantly reduced Aβ accumulation in the subiculum andconnected brain regions, while also enhancing cognitive function in AD mice. Supporting these findings, single-nucleus RNAsequencing (snRNA-seq) data from human AD patients revealed that PV expression in GABAergic neurons peaks at early stages ofthe disease, further reinforcing the role of PV interneuron hyperactivity in early AD progression. Additionally, PV interneuroninhibition restored protein homeostasis by normalizing GABAergic synapses, improving lysosomal function, and promoting APPdegradation via K63-linked ubiquitination. These results provide critical insights into the cellular mechanisms that drive early Aβpathology in the subiculum, positioning subicular PV-INs as promising therapeutic targets for early intervention in AD.Molecular Psychiatry;