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We previously reported that Klotho lowered A\u03b2 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\u2010month\u2010old APP\/PS1 mice by injecting lentivirus that carried full\u2010length mouse Klotho cDNA in the lateral ventricle of the brain. We examined the effects of Klotho overexpression on cognition, A\u03b2 burden, A\u03b2\u2010related neuropathology, microglia transformation, and A\u03b2 transport systems in vivo. Additionally, we investigated the effects of Klotho on A\u03b2 transport at the blood\u2013cerebrospinal 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 A\u03b2 burden, neuronal and synaptic loss and cognitive deficits in aged APP\/PS1 mice. Klotho treatment significantly inhibited NACHT, LRR, and PYD domain\u2010containing protein 3 (NLRP3) and the subsequent transformation of microglia to the M2 type that may enhance microglia\u2010mediated A\u03b2 clearance. Meanwhile, Klotho overexpression also regulated A\u03b2 transporter expression, which may promote A\u03b2 transporter\u2010mediated A\u03b2 clearance. Moreover, the ability of HCPEpiCs to transport A\u03b2 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.<\/jats:p>","DOI":"10.1111\/acel.13239","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T10:10:25Z","timestamp":1600683025000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["Klotho overexpression improves amyloid\u2010\u03b2 clearance and cognition in the APP\/PS1 mouse model of Alzheimer's disease"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-4949","authenticated-orcid":false,"given":"Yue","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen\u2010Ye","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Hong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting\u2010Ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010Rong","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.05.002"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2017.10.023"},{"key":"e_1_2_9_4_1","first-page":"1233","article-title":"Klotho, stem cells, and aging","volume":"10","author":"Bian A.","year":"2015","journal-title":"Clinical Interventions in 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