Amyloid β-dependent neuronal silencing through synaptic decoupling

• 成果类型: Article
• 署名作者: Zhang, Yonghai; Chen-Engerer, Hsing-Jung; Zhang, Kuan; Zott, Benedikt; Varga, Zsuzsanna; Chen, Yang; Chen, Xiaowei; Jia, Hongbo; Sakmann, Bert; Nelken, Israel; Konnerth, Arthur
• 署名单位: Technical University of Munich; University of Munich; Technical University of Munich; Army Medical University; Army Medical University; Technical University of Munich; Technical University of Munich; Leibniz Association; Leibniz Institut fur Neurobiologie (LIN); Hebrew University of Jerusalem; Hebrew University of Jerusalem
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10976
• DOI: 10.1073/pnas.2515113122
• 发表日期: 2025-09-02
• 关键词: mild cognitive impairment; alzheimers-disease; mouse model; hippocampal activation; hyperactivity; single; tau; inhibition; networks; hyperexcitability

摘要

Amyloid n (An)-dependent circuit dysfunction in Alzheimer's disease (AD) is determined by a puzzling mix of hyperactive and inactive (silent) brain neurons. Recent studies identified excessive glutamate accumulation as a key An-dependent determinant of hyperactivity. The cellular mechanisms underlying neuronal silence depend on both An and tau protein pathologies, with an unknown role of An. Here, by using single-cell-initiated rabies virus (RV) tracing in mouse models of n-amyloidosis, we demonstrate that the presynaptic connectivity of silent, but not that of hyperactive, neurons is severely disrupted. Furthermore, silent neurons display a major spine loss and strongly suppressed synaptic activity. Thus, we suggest that synaptic decoupling is an An-dependent cellular mechanism underlying progressive neuronal silencing and a critical factor for the cognitive impairments encountered in AD.