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. J. Neurochem. 106:475–485; 2008). 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 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 insulin/IGF signaling (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 and 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 (AD)-like cognitive impairment in ‘normal’ mice.

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

“…It has been reported that long-term HFFD feeding causes GSK3b activation associated with tau phosphorylation at PHF-1 (S396/404) and T231 (ref. 26). Tau phosphorylation sites have been extensively studied in terms of the impairment for microtubule binding and the formation of insoluble neurofibrillary tangles that cause multiple anomalies, from axonal dysfunction to the loss of neuronal integrity and neuronal death.…”

“…Tau phosphorylation sites have been extensively studied in terms of the impairment for microtubule binding and the formation of insoluble neurofibrillary tangles that cause multiple anomalies, from axonal dysfunction to the loss of neuronal integrity and neuronal death. [24][25][26]35 Finally, we examined whether the biochemical, morphologic, and structural changes found in the hippocampus of HFFD rats were accompanied by reactive astrocyte activation. One of the pathologic features of obesity and InsRes is inflammation, and it has been described that central inflammation has an impact on brain function possibly through the import of inflammatory cytokines and immune cells into the central nervous system.…”

“…In this regard, it has been reported that long-term high-fat (not fructose) feeding in mice produced alterations in Akt and GSK3b signaling in the hippocampus. 26 Since virtually all studies on hippocampal dysfunction due to HFFD administration have addressed the impact of long-term feeding, for more than 4 weeks, the present work aimed to investigate early biochemical and structural changes in the hippocampus after short-term consumption of HFFD. We found that obesity and InsRes caused by 7 days of HFFD intake were sufficient to alter insulin signaling in the hippocampus associated with decreased complexity of neurites, reduced synaptic markers, modifications of MAPs, and increased number of reactive astrocytes and microglia.…”

Resveratrol Protects against High-Fat Diet Induced Renal Pathological Damage and Cell Senescence by Activating SIRT1

“…37) In addition, the alteration of some key proteins or signaling pathways is similar under HFD or HG culture. For example, they both have impaired insulin-like growth factor 1 (IGF-1) signaling, 38,39) and they both target p53 protein, 40,41) which plays significant roles in aging and apoptosis. Therefore, even they are different biochemical changes, the HG culture condition may be acceptable to mimic the effect of HFD in the in vitro study.…”

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

“…Such results indicate that cellular accumulation of sphingolipids could induce key cytopathological changes characteristic of AD, such as alterations to the autophagic/lysosomal system, increased generation of Aβ and accumulation of APP-CTFs in autophagic vesicles at dystrophic neurites, as occurs in an agedependent manner in transgenic mouse models of AD [58]. Interestingly, a cholesterolenriched diet in healthy mice also leads to insulin-like growth factor 1 (IGF1) impairment and insulin-mediated pro-survival signaling, which in turn promotes tau hyperphosphorylation in neurons [59]. Together, this evidence suggests that altered cholesterol/sphingolipid homeostasis may promote the neurite pathology, tau hyperphosphorylation, and amyloidogenic APP processing in AD.…”