Alzheimer's disease (AD) is histopathologically characterized by Aβ plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsα to hippocampal slices, indicating a homeostatic function of APPsα on a rapid time scale. Further, AAV-mediated in vivo expression of APPsα restored normal spine density of CA1 neurons even at stages of advanced Tau pathology not only in P301S mice, but also in independent THY-Tau22 mice. Strikingly, when searching for the mechanism underlying aberrantly increased LTP in P301S mice, we identified an early and progressive loss of major GABAergic interneuron subtypes in the hippocampus of P301S mice, which may lead to reduced GABAergic inhibition of principal cells. Interneuron loss was paralleled by deficits in nest building, an innate behavior highly sensitive to hippocampal impairments. Together, our findings indicate that APPsα has therapeutic potential for Tau-mediated synaptic dysfunction and suggest that loss of interneurons leads to disturbed neuronal circuits that compromise synaptic plasticity as well as behavior.

SIGNIFICANCE STATEMENT Our findings indicate, for the first time, that APPsα has the potential to rescue Tau-induced spine loss and abnormal synaptic plasticity. Thus, APPsα might have therapeutic potential not only because of its synaptotrophic functions, but also its homeostatic capacity for neuronal network activity. Hence, APPsα is one of the few molecules which has proven therapeutic effects in mice, both for Aβ- and Tau-dependent synaptic impairments and might therefore have therapeutic potential for patients suffering from AD or primary tauopathies. Furthermore, we found in P301S mice a pronounced reduction of inhibitory interneurons as the earliest pathologic event preceding the accumulation of hyperphosphorylated Tau species. This loss of interneurons most likely disturbs neuronal circuits that are important for synaptic plasticity and behavior.

阿尔茨海默氏病 (AD) 的组织病理学特征是 Aβ 斑块和过度磷酸化 Tau 物质的积累，后者也是原发性 Tau 病的关键标志。虽然 Aβ 是由淀粉样变性 APP 加工产生的，但沿着竞争性非淀粉样变性途径的 APP 加工会导致神经营养性和突触营养性 APPsα 的分泌。最近，我们证明了 APPsα 对转基因 AD 模型小鼠具有治疗作用并可挽救 Aβ 依赖性损伤。在这里，我们检查了 APPsα 减轻P301S小鼠（男女）中 Tau 诱导的突触缺陷的潜力，P301S 小鼠是一种广泛使用的 tau 病小鼠模型。突触可塑性分析显示P301S中的 LTP 异常增加可以通过将纳摩尔量的 APPsα 急性应用到海马切片来使小鼠正常化，表明 APPsα 在快速时间尺度上的稳态功能。此外，AAV 介导的 APPsα体内表达恢复了 CA1 神经元的正常脊柱密度，即使在晚期 Tau 病理学阶段，不仅在P301S小鼠中，而且在独立的 THY-Tau22小鼠中也是如此。引人注目的是，在寻找P301S小鼠 LTP 异常增加的潜在机制时，我们发现 P301S 海马体中主要GABAergic中间神经元亚型的早期和进行性丧失小鼠，这可能导致主要细胞的 GABAergic 抑制减少。中间神经元丢失伴随着筑巢缺陷，这是一种对海马体损伤高度敏感的先天行为。总之，我们的研究结果表明 APPsα 对 Tau 介导的突触功能障碍具有治疗潜力，并表明中间神经元的丢失会导致神经元回路受到干扰，从而损害突触可塑性和行为。

意义声明我们的研究结果首次表明，APPsα 有可能挽救 Tau 诱导的脊柱丢失和异常的突触可塑性。因此，APPsα 可能具有治疗潜力，不仅因为它具有突触营养功能，而且还因为它对神经元网络活动的稳态能力。因此，APPsα 是为数不多的已在小鼠中证明对 Aβ 和 Tau 依赖性突触损伤有治疗作用的分子之一，因此可能对患有 AD 或原发性 tau 病的患者具有治疗潜力。此外，我们在P301S中发现小鼠抑制性中间神经元的显着减少是过度磷酸化 Tau 物种积累之前最早的病理事件。这种中间神经元的丢失很可能会扰乱对突触可塑性和行为很重要的神经回路。