Hyperactivity of subicular parvalbumin interneurons drives early amyloid pathology and cognitive deficits in Alzheimer's disease.

Atrophy of the subiculum is the earliest hippocampal anatomical marker of Alzheimer's disease (AD) and is closely associated with early cognitive decline. However, the underlying mechanisms driving this vulnerability remain unclear. In this study, using the 5×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 in the subiculum. Further investigation revealed that parvalbumin (PV) interneurons (PV-INs) were key drivers of Aβ pathology, exhibiting pronounced hyperactivity during the initial stages of AD. Targeted inhibition of this PV interneuron hyperactivity at the onset of AD, using chemogenetic approaches and PV downregulation, significantly reduced Aβ accumulation in the subiculum and connected brain regions, while also enhancing cognitive function in AD mice. Supporting these findings, single-nucleus RNA sequencing (snRNA-seq) data from human AD patients revealed that PV expression in GABAergic neurons peaks at early stages of the disease, further reinforcing the role of PV interneuron hyperactivity in early AD progression. Additionally, PV interneuron inhibition restored protein homeostasis by normalizing GABAergic synapses, improving lysosomal function, and promoting APP degradation via K63-linked ubiquitination. These results provide critical insights into the cellular mechanisms that drive early Aβ pathology in the subiculum, positioning subicular PV-INs as promising therapeutic targets for early intervention in AD.