Abnormally phosphorylated tau, an early neuropathologic marker of Alzheimer’s disease (AD), first occurs in the brain’s entorhinal cortex layer II (ECII) and then spreads to the CA1 field of the hippocampus. Animal models of tau propagation aiming to recapitulate this phenomenon mostly show tau transfer from ECII stellate neurons to the dentate gyrus, but tau pathology in the dentate gyrus does not appear until advanced stages of AD. Wolframin-1–expressing (Wfs1⁺) pyramidal neurons have been shown functionally to modulate hippocampal CA1 neurons in mice. Here, we report that Wfs1⁺ pyramidal neurons are conserved in the ECII of postmortem human brain tissue and that Wfs1 colocalized with abnormally phosphorylated tau in brains from individuals with early AD. Wfs1⁺ neuron–specific expression of human P301L mutant tau in mouse ECII resulted in transfer of tau to hippocampal CA1 pyramidal neurons, suggesting spread of tau pathology as observed in the early Braak stages of AD. In mice expressing human mutant tau specifically in the ECII brain region, electrophysiological recordings of CA1 pyramidal neurons showed reduced excitability. Multielectrode array recordings of optogenetically stimulated Wfs1⁺ ECII axons resulted in reduced CA1 neuronal firing. Chemogenetic activation of CA1 pyramidal neurons showed a reduction in c-fos⁺ cells in the CA1. Last, a fear conditioning task revealed deficits in trace and contextual memory in mice overexpressing human mutant tau in the ECII. This work demonstrates tau transfer from the ECII to CA1 in mouse brain and provides an early Braak stage preclinical model of AD.

中文翻译：

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内嗅皮层中表达 Wolframin-1 的神经元将 tau 传播到 CA1 神经元并损害小鼠的海马记忆

异常磷酸化的 tau 蛋白是阿尔茨海默病 (AD) 的早期神经病理学标志物，首先出现在大脑的内嗅皮质层 II (ECII)，然后扩散到海马的 CA1 区。旨在概括这一现象的 tau 传播动物模型主要显示 tau 从 ECII 星状神经元转移到齿状回，但齿状回中的 tau 病理直到 AD 晚期才出现。已显示表达 Wolframin-1 (Wfs1 ⁺ ) 的锥体神经元在功能上可调节小鼠海马 CA1 神经元。在这里，我们报告 Wfs1 ⁺锥体神经元在死后人脑组织的 ECII 中是保守的，并且 Wfs1 与早期 AD 个体大脑中异常磷酸化的 tau 共定位。WFS1 ⁺人 P301L 突变体 tau 在小鼠 ECII 中的神经元特异性表达导致 tau 转移到海马 CA1 锥体神经元，表明在 AD 早期 Braak 阶段观察到的 tau 病理学扩散。在 ECII 脑区特异性表达人类突变 tau 的小鼠中，CA1 锥体神经元的电生理记录显示兴奋性降低。光遗传学刺激的 Wfs1 ⁺ ECII 轴突的多电极阵列记录导致 CA1 神经元放电减少。CA1 锥体神经元的化学遗传学激活显示 c-fos ⁺CA1 中的细胞。最后，恐惧条件反射任务揭示了在 ECII 中过度表达人类突变体 tau 的小鼠的痕迹和上下文记忆缺陷。这项工作展示了小鼠大脑中从 ECII 到 CA1 的 tau 转移，并提供了 AD 的早期 Braak 阶段临床前模型。