Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by the presence of amyloid‐β (Aβ) plaques. We previously reported that Klotho lowered Aβ levels in the brain and protected against cognitive deficits in amyloid precursor protein/presenilin 1(APP/PS1) mice. However, the underlying mechanism remains unclear. In this study, we induced intracerebral Klotho overexpression in 13‐month‐old APP/PS1 mice by injecting lentivirus that carried full‐length mouse Klotho cDNA in the lateral ventricle of the brain. We examined the effects of Klotho overexpression on cognition, Aβ burden, Aβ‐related neuropathology, microglia transformation, and Aβ transport systems in vivo. Additionally, we investigated the effects of Klotho on Aβ transport at the blood–cerebrospinal fluid barrier by knocking down Klotho in primary human choroid plexus epithelial cells (HCPEpiCs). The upregulation of Klotho levels in the brain and serum significantly ameliorated Aβ burden, neuronal and synaptic loss and cognitive deficits in aged APP/PS1 mice. Klotho treatment significantly inhibited NACHT, LRR, and PYD domain‐containing protein 3 (NLRP3) and the subsequent transformation of microglia to the M2 type that may enhance microglia‐mediated Aβ clearance. Meanwhile, Klotho overexpression also regulated Aβ transporter expression, which may promote Aβ transporter‐mediated Aβ clearance. Moreover, the ability of HCPEpiCs to transport Aβ in vitro was also significantly impaired by Klotho knockdown. Given the neuroprotective effect of Klotho overexpression, the present findings suggest that Klotho should be further investigated as a potential therapeutic target for AD.

中文翻译：

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Klotho过表达可改善Alzheimer病APP / PS1小鼠模型中的淀粉样β清除率和认知能力。

阿尔茨海默氏病（AD）是最普遍的痴呆类型，其特征在于存在淀粉样β（Aβ）斑块。我们先前曾报道过Klotho降低了大脑中Aβ的水平，并防止淀粉样蛋白前体蛋白/早老素1（APP / PS1）小鼠出现认知缺陷。但是，其潜在机制仍不清楚。在这项研究中，我们通过注射携带全长小鼠Klotho cDNA的慢病毒，在13个月大的APP / PS1小鼠中诱导脑内Klotho过表达。我们检查了Klotho过表达对体内认知，Aβ负担，Aβ相关神经病理学，小胶质细胞转化和Aβ转运系统的影响。另外，我们通过击倒人类初级脉络丛神经上皮细胞（HCPEpiCs）中的Klotho，研究了Klotho对血脑脊髓液屏障Aβ转运的影响。脑和血清中Klotho水平的上调显着改善了老年APP / PS1小鼠的Aβ负担，神经元和突触丧失以及认知缺陷。Klotho处理显着抑制了含有NACHT，LRR和PYD域的蛋白3（NLRP3），随后小胶质细胞转变为M2型，这可能会增强小胶质细胞介导的Aβ清除率。同时，Klotho过表达还调节Aβ转运蛋白的表达，这可能会促进Aβ转运蛋白介导的Aβ清除。此外，Klotho敲除也大大削弱了HCPEpiCs在体外转运Aβ的能力。鉴于Klotho过表达的神经保护作用，