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In this study, we found a substantial decline in isocitrate dehydrogenase 3\u03b2 (IDH3\u03b2) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice\u2019s brains. Further investigations demonstrated that the knockdown of IDH3\u03b2 induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3\u03b2, the elevated PAX6 in turn inhibited the expression of IDH3\u03b2, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3\u03b2 and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3\u03b2-lactate-PAX6-IDH3\u03b2. Breaking this loop by upregulating IDH3\u03b2 or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.<\/jats:p>","DOI":"10.1038\/s41392-024-01812-5","type":"journal-article","created":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T23:02:08Z","timestamp":1714345328000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["A positive feedback inhibition of isocitrate dehydrogenase 3\u03b2 on paired-box gene 6 promotes Alzheimer-like pathology"],"prefix":"10.1038","volume":"9","author":[{"given":"Xin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-tao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-zhao","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-ning","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-ting","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Zhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"1812_CR1","doi-asserted-by":"publisher","first-page":"e100751","DOI":"10.1136\/gpsych-2022-100751","volume":"35","author":"R Ren","year":"2022","unstructured":"Ren, R. et al. 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