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<p>Current therapeutic strategies for Alzheimer’s disease (AD) target amyloid-beta (Aβ) fibrils and high molecular weight protofibrils associated with plaques, but molecular cascades associated with AD may drive neural systems failure before Aβ plaque deposition in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in a freely behaving mouse model of AD before Aβ plaques accumulated, we detected marked impairments of hippocampal systems function: In a spatial behavioral task, phase-amplitude coupling (PAC) of the hippocampal theta and gamma oscillations was impaired and place cell calcium fluctuations were hyper-synchronized with the theta oscillation. These changes were not observed in REM sleep. In subsequent slow wave sleep (SWS), place cell reactivation was reduced. These degraded neural functions underlying memory encoding and consolidation support targeting pathological processes of the pre-plaque phase of AD to treat and prevent hippocampal impairments.</p>

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Impaired hippocampal circuit function underlying memory encoding and consolidation precede robust Aβ deposition in a mouse model of alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Hanyan Li,
  • Zhuoyang Zhao,
  • Aline Fassini,
  • Han K. Lee,
  • Reese J. Green,
  • Stephen N. Gomperts

摘要

Current therapeutic strategies for Alzheimer’s disease (AD) target amyloid-beta (Aβ) fibrils and high molecular weight protofibrils associated with plaques, but molecular cascades associated with AD may drive neural systems failure before Aβ plaque deposition in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in a freely behaving mouse model of AD before Aβ plaques accumulated, we detected marked impairments of hippocampal systems function: In a spatial behavioral task, phase-amplitude coupling (PAC) of the hippocampal theta and gamma oscillations was impaired and place cell calcium fluctuations were hyper-synchronized with the theta oscillation. These changes were not observed in REM sleep. In subsequent slow wave sleep (SWS), place cell reactivation was reduced. These degraded neural functions underlying memory encoding and consolidation support targeting pathological processes of the pre-plaque phase of AD to treat and prevent hippocampal impairments.