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<p>Alzheimer’s disease (AD) is characterized by aberrant neuronal oscillations, notably reduced power in the slow gamma and beta bands, which are critical for cognitive functions. Optogenetic stimulation presents a promising therapeutic approach, but its application for AD requires identifying optimal targets and stimulation parameters. To address this, we develop a computational neuron-astrocyte model incorporating Aβ pathology to investigate the efficacy of optogenetic stimulation in restoring these abnormal rhythms. We first simulate AD pathophysiology by enhancing astrocyte membrane calcium permeability and ryanodine receptor sensitivity, which successfully recapitulates the experimental characteristic decrease in slow gamma power and beta power. Subsequently, we apply optogenetic stimulation targeting two key neuron elements: PV interneuron and astrocyte. Power spectrum analysis reveals that stimulation at both targets could effectively reverse the AD-related power reductions. A systematic parameter analysis further identifies that 40&#xa0;Hz stimulation is optimal for restoring PV interneuron slow gamma power, while 10&#xa0;Hz was most effective for enhancing PY neuron beta power. Our results demonstrate that astrocyte-targeted stimulation is particularly effective in restoring PY neuron beta band power. Significantly, this study successfully replicates key electrophysiological findings from AD models and therapeutic outcomes of drug treatments, providing a novel theoretical framework for exploring optogenetic interventions in AD. By identifying PV interneuron and astrocyte as feasible targets and defining effective parameter ranges, this work offers valuable insights for guiding future experimental and clinical applications of optogenetic stimulation therapy for AD.</p>

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Optogenetic stimulation regulates abnormal neuronal rhythm in an Alzheimer’s disease model

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • JiangNing Wang,
  • XiaoLi Yang

摘要

Alzheimer’s disease (AD) is characterized by aberrant neuronal oscillations, notably reduced power in the slow gamma and beta bands, which are critical for cognitive functions. Optogenetic stimulation presents a promising therapeutic approach, but its application for AD requires identifying optimal targets and stimulation parameters. To address this, we develop a computational neuron-astrocyte model incorporating Aβ pathology to investigate the efficacy of optogenetic stimulation in restoring these abnormal rhythms. We first simulate AD pathophysiology by enhancing astrocyte membrane calcium permeability and ryanodine receptor sensitivity, which successfully recapitulates the experimental characteristic decrease in slow gamma power and beta power. Subsequently, we apply optogenetic stimulation targeting two key neuron elements: PV interneuron and astrocyte. Power spectrum analysis reveals that stimulation at both targets could effectively reverse the AD-related power reductions. A systematic parameter analysis further identifies that 40 Hz stimulation is optimal for restoring PV interneuron slow gamma power, while 10 Hz was most effective for enhancing PY neuron beta power. Our results demonstrate that astrocyte-targeted stimulation is particularly effective in restoring PY neuron beta band power. Significantly, this study successfully replicates key electrophysiological findings from AD models and therapeutic outcomes of drug treatments, providing a novel theoretical framework for exploring optogenetic interventions in AD. By identifying PV interneuron and astrocyte as feasible targets and defining effective parameter ranges, this work offers valuable insights for guiding future experimental and clinical applications of optogenetic stimulation therapy for AD.