Amyloid β–dependent neuronal silencing through synaptic decoupling

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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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-08-28
DOI
https://doi.org/10.1073/pnas.2515113122
Citations
1
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
1.16

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Amyloid β–dependent neuronal silencing through synaptic decoupling

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Amyloid β–dependent neuronal silencing through synaptic decoupling

Zsuzsanna Varga, Benedikt Zott, Arthur Konnerth, Israel Nelken, Hsing-Jung Chen-Engerer, Bert Sakmann, Kuan Zhang, Yonghai Zhang, Jia Hongbo, Yang Chen, Xiaowei Chen
article en
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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.

Proceedings of the National Academy of SciencesVol. 122(35)
Army Medical University (CN), Hebrew University of Jerusalem (IL), Munich Cluster for Systems Neurology (DE), Max Planck Institute for Intelligent Systems (DE), Max Planck Institute for Biological Intelligence, Technical University of Munich (DE), Leibniz Institute for Neurobiology (DE)
Deutsche Forschungsgemeinschaft, Ludwig-Maximilians-Universität München
Openalex Percentile: Top 18%
Alzheimer's disease research and treatments
1.16
DOIOpen Access PDFOpenAlex
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