Basal forebrain parvalbumin neuron dysfunction links network oscillation deficits to hippocampal pathology in Alzheimer's disease.

Authors

Eunjin Hwang, Hyun Soo Shim, Seung Chan Kim, Min-Ho Nam, Seung Jae Hyeon, Hea-Jin Kim, Ji Eun Kim, Hyeok Ju Park, Jiwan Woo, Eun Mi Hwang, Thor Stein, Junghee Lee, Jee Hyun Choi, Hoon Ryu

Published in

Research square. Jun 26, 2026. Epub Jun 26, 2026.

Abstract

Background Basal forebrain (BF) degeneration is a key pathological feature of Alzheimer's disease (AD) and is closely associated with cognitive decline. Although parvalbumin (PV)-expressing neurons are abundant in the BF and are important regulators of cortical network activity, their contribution to AD pathogenesis remains poorly understood. Methods To investigate the role of BF-PV neurons in AD, we examined the effects of PV knockdown in the BF of APP/PS1 mice. Electrophysiological recordings, behavioral analyses, retrograde tracing, hippocampal transcriptome profiling, and integrative computational analyses, including meta-correlation analysis and artificial neural network (ANN) modeling, were performed to assess the impact of BF-PV loss on neural network activity, hippocampal pathology, and cognitive function. Results BF-PV knockdown disrupted theta oscillations and theta-gamma coupling in the parietal cortex and impaired hippocampal synaptic activity and memory-related behaviors in mice. Retrograde tracing demonstrated that BF neuronal circuits project directly to the hippocampus. Transcriptome analysis revealed that BF-PV knockdown increased amyloidosis- and microvessel-associated gene signatures while reducing synaptic plasticity-related gene expression in the hippocampus. Furthermore, meta-correlation analyses and ANN modeling indicated that BF-PV dysfunction strongly predicts hippocampal pathology, disrupted EEG coupling, and behavioral abnormalities in AD mice. Conclusions These findings identify BF-PV neuronal dysfunction as an important contributor to hippocampal pathology, neural network dysregulation, and cognitive impairment in AD, highlighting BF-PV neurons as a potential mechanistic link between BF degeneration and AD progression.

PMID:
42396515
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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