| Amyloid β–dependent neuronal silencing through synaptic decouplingpling
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| June 10, 2025
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| Yonghai Zhang, Hsing-Jung Chen-Engerer,Kuan Zhang,Benedikt Zott,Zsuzsanna Varga,Yang Chen,Xiaowei Chen,Hongbo Jia,Bert Sakmann, Israel Nelken, Arthur Konnerth
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| PNAS
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 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..
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