In Alzheimer’s disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology.

在阿尔茨海默病 (AD) 中，β-淀粉样蛋白 (Aβ) 和 tau 蛋白沉积在大脑中，神经元网络过度兴奋是潜在的疾病机制，但其原因仍不清楚。在这里，我们使用协作交叉（CC）正向遗传学小鼠平台来识别神经元过度兴奋的修饰基因。我们发现 LAMP5 是小鼠过度兴奋的新型调节剂，对于不同中间神经元群体的生存至关重要。有趣的是，突触 LAMP5 在 AD 大脑中丢失，并且 LAMP5 中间神经元在不同 AD 小鼠模型中退化。 LAMP5 的基因减少增强了 Aβ 和 tau 驱动的 AD 小鼠模型的功能缺陷和神经元网络超同步性。为此，我们的工作定义了 LAMP5 中间神经元在 AD 和 tau 病理学痴呆的神经元网络过度兴奋中的第一个特定功能。