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To model this pathological link, our AD-like model was developed by feeding Wistar male rats a high-fat diet with fructose in drinking water (HFFD) for 8 weeks, followed by a single dose of lipopolysaccharide (LPS). This group was compared with a normal control group fed a standard diet and a \u03b2-hydroxybutyrate (BHB)-treated group (125 mg\/kg, p.o.), administered starting 3 h after LPS and continuing for 1 week. The results demonstrate that BHB treatment illuminated cognitive gains, as indicated by the Y-maze, Morris water maze, and novel object recognition tests. In addition, it preserved hippocampal cytoarchitecture, reduced neurodegeneration, and attenuated amyloid plaques and phosphorylated Tau deposition. Cellularly, BHB restored critical molecular mechanisms, including increased lysosomal-associated membrane protein 2A (LAMP2A) hippocampal content as the main marker of chaperone-mediated autophagy (CMA), along with the chaperon protein Hsp70. Moreover, BHB alleviated neuroinflammation by inhibiting the nucleotide-binding domain, leucine-rich\u2013containing family,\u00a0and pyrin domain\u2013containing-3 (NLRP3) inflammasome activation alongside the downstream targets cleaved caspase-1 and IL-1\u03b2\/IL-18 cytokines. BHB also reduced pyroptotic markers, caspase-11 and gasdermin-N, and microglia-induced inflammation as it shifted microglial polarization toward the neuroprotective M2 phenotype. Finally, BHB normalized hippocampal neurotransmitter levels of the inhibited acetylcholine and serotonin. These findings support BHB as a promising, multifaceted treatment for AD, highlighting the roles of CMA, Hsp70, and 5-HT in slowing disease progression and improving cognitive function.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10787-025-01754-6","type":"journal-article","created":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T04:38:09Z","timestamp":1746333489000},"page":"3461-3477","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Chaperone-mediated autophagy, heat shock protein 70, and serotonin: novel targets of beta-hydroxybutyrate in HFFD\/LPS-induced sporadic Alzheimer\u2019s disease model"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7419-0124","authenticated-orcid":false,"given":"Reem A.","family":"Mohamed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalaal M.","family":"Abdallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan S.","family":"El-Abhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,4]]},"reference":[{"key":"1754_CR1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/0304-3940(96)12421-6","volume":"206","author":"V Amin","year":"1996","unstructured":"Amin V, Cumming DV, Latchman DS (1996) Over-expression of heat shock protein 70 protects neuronal cells against both thermal and ischaemic stress but with different efficiencies. 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