Chaperone‑mediated autophagy, heat shock protein 70, and serotonin: novel targets of beta‑hydroxybutyrate in HFFD/ LPS‑induced sporadic Alzheimer’s disease model
Date
2025-05-04
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Inflammopharmacology
Series Info
Inflammopharmacology ; 2025 , Article number 102444
Scientific Journal Rankings
Abstract
Sporadic Alzheimer’s disease (AD), which accounts for the majority of cases, is sturdily infuenced by lifestyle factors such
as dietary habits, obesity, and diabetes, leading to its classifcation as Type 3 diabetes. 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 β-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 neuroinfammation by inhibiting the nucleotide-binding domain, leucine-rich–containing family, and pyrin domain–containing-3 (NLRP3)
infammasome activation alongside the downstream targets cleaved caspase-1 and IL-1β/IL-18 cytokines. BHB also reduced
pyroptotic markers, caspase-11 and gasdermin-N, and microglia-induced infammation as it shifted microglial polarization
toward the neuroprotective M2 phenotype. Finally, BHB normalized hippocampal neurotransmitter levels of the inhibited
acetylcholine and serotonin. These fndings 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.
Description
SJR 2024
1.269 Q1
H-Index
74
Keywords
Alzheimer disease, Chaperone-mediated autophagy, Hsp70, NLRP3, Serotonin, β-hydroxybutyrate
Citation
Mohamed, R. A., Abdallah, D. M., & El-Abhar, H. S. (2025b). Chaperone-mediated autophagy, heat shock protein 70, and serotonin: novel targets of beta-hydroxybutyrate in HFFD/LPS-induced sporadic Alzheimer’s disease model. Inflammopharmacology. https://doi.org/10.1007/s10787-025-01754-6