title: Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet.
abstract: Previous studies demonstrated that a high fat/high cholesterol (HFC) diet results in a loss of working memory in mice correlated with neuroinflammatory changes and increased AβPP processing (Thirumangalakudi et al. (2008) J Neurochem 106, 475-485). To further explore the nature of the molecular correlates of cognitive impairment, in this study, we examined changes in tau phosphorylation, insulin/IGF-1 signaling (IIS) including GSK3, and levels of specific synaptic proteins. Immunoblot analysis of hippocampal tissue from C57BL/6 mice fed HFC for 2 months with anti-phospho-tau (i.e., PHF1 and phospho-Thr-231 tau) antibodies demonstrated the presence of hyperphosphorylated tau. The tau phosphorylation correlated with activated GSK3, a prominent tau kinase normally kept inactive under the control of IIS. That IIS itself was impaired due to the hyperlipidemic diet was confirmed by a down-regulation of insulin receptor substrate-1 and phospho-Akt levels. Although no significant changes in the levels of the pre-synaptic protein (i.e., synaptophysin) in response to HFC were apparent in immunoblot analysis, there was a clear down-regulation of the post-synaptic protein, PSD95, and drebrin, a dendritic spine-specific protein, indicative of altered synaptic plasticity. The results, in concert with previous findings with the same model, suggest that high dietary fat/cholesterol elicits brain insulin resistance and altered IIS leading to Alzheimer's disease-like cognitive impairment in 'normal' mice.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. bhatnr@musc.edu
authors.forename: Narayan R
authors.initials: NR
authors.lastname: Bhat
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Thirumangalakudi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000009:adverse effects / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002791:Cholesterol, Dietary; D007328:Insulin; C519530:insulin-like growth factor-1, mouse; D016875:tau Proteins; D007334:Insulin-Like Growth Factor I