Amyloid β–dependent neuronal silencing through synaptic decoupling

Zhang, Yonghai ; Chen-Engerer, Hsing-Jung; Zhang, Kuan; Zott, Benedikt; Varga, Zsuzsanna; Chen, Yang ; Chen, Xiaowei; Jia, Hongbo; Sakmann, Bert; Nelken, Israel und Konnerth, Arthur (2025): Amyloid β–dependent neuronal silencing through synaptic decoupling. In: Proceedings of the National Academy of Sciences of the United States of America, Bd. 122, Nr. 35, e2515113122

Abstract

Amyloid β (Aβ)-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 Aβ-dependent determinant of hyperactivity. The cellular mechanisms underlying neuronal silence depend on both Aβ and tau protein pathologies, with an unknown role of Aβ. Here, by using single-cell-initiated rabies virus (RV) tracing in mouse models of β-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 Aβ-dependent cellular mechanism underlying progressive neuronal silencing and a critical factor for the cognitive impairments encountered in AD.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0027-8424
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 118803580