title: Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain.
abstract: Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTOR(ser2448), AKT(thr308) and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight into the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions.
authors.affiliation: Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70810, USA. Electronic address: Kalavathidasuri@gmail.com.
authors.forename: Kalavathi
authors.initials: K
authors.lastname: Dasuri
authors.affiliation: Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70810, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70810, USA.
authors.forename: Sun O K Fernandez
authors.initials: SO
authors.lastname: Kim
authors.affiliation: Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70810, USA.
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
authors.affiliation: Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70810, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D059305:Diet, High-Fat / Q000009:adverse effects*; D000077265:Donepezil / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D000077265:Donepezil; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Aging; Brain; Donepezil; High fat diet; Neurodegenerative disorders; Neuroinflammation; Obesity; mTOR pathway