Detrimental effects of diet-induced obesity on τ pathology are independent of insulin resistance in τ transgenic mice

Abstract

The τ pathology found in Alzheimer disease (AD) is crucial in cognitive decline. Midlife development of obesity, a major risk factor of insulin resistance and type 2 diabetes, increases the risk of dementia and AD later in life. The impact of obesity on AD risk has been suggested to be related to central insulin resistance, secondary to peripheral insulin resistance. The effects of diet-induced obesity (DIO) on τ pathology remain unknown. In this study, we evaluated effects of a high-fat diet, given at an early pathological stage, in the THY-Tau22 transgenic mouse model of progressive AD-like τ pathology. We found that early and progressive obesity potentiated spatial learning deficits as well as hippocampal τ pathology at a later stage. Surprisingly, THY-Tau22 mice did not exhibit peripheral insulin resistance. Further, pathological worsening occurred while hippocampal insulin signaling was upregulated. Together, our data demonstrate that DIO worsens τ phosphorylation and learning abilities in τ transgenic mice independently from peripheral/central insulin resistance.

FIG. 1.

HFD leads to obesity in absence of insulin resistance in THY-Tau22 mice. A: Progressive establishment of a diet-induced obesity in WT and THY-Tau22 mice (WC vs. WH, P < 0.001; TC vs. TH, P < 0.001, using 2W-ANOVA). B and C: Glucose (B) and insulin (C) levels at completion of experiment. D and E: Intraperitoneal glucose tolerance test demonstrated significant and similar impairments in HFD-fed mice regardless of genotype (WC vs. WH and TC vs. TH, P < 0.001 using 2W-ANOVA). F and G: Insulin tolerance test demonstrated significant attenuation of glucose lowering following insulin injection in WH mice as compared with WC animals (P < 0.001 using 2W-ANOVA). Conversely, TH mice were not significantly different from TC animals (P = 0.20 vs. TC group using 2W-ANOVA). E and G represent areas under the curve (AUC) calculated from data presented in F and H, respectively. Results are expressed as means ± SEM. °°P < 0.01, °°°P < 0.001 vs. respective chow; ^#P < 0.05, ^###P < 0.001 vs. TH mice using 1W-ANOVA. Open circles/open bars, WC; black squares/black bars, TC; crossed circles/dashed bars, WH; open squares/black dashed bars, TH.

FIG. 2.

HFD potentiates spatial learning impairments in THY-Tau22 mice. TC animals exhibited significantly increased escape latency (A) and path length (B) as compared with WC animals. Although HFD did not exert significant influence on both parameters in WT animals, escape latency and path length were further increased in TH mice as compared with TC animals. Results are expressed as means ± SEM. WC vs. TC: *P < 0.05, **P < 0.01; TC vs. TH: #P < 0.05 using 2W-ANOVA. Open circles, WC; black squares, TC; crossed circles, WH; open squares, TH.

FIG. 3.

HFD increases hippocampal τ phosphorylation in THY-Tau22 mice. A: Representative two-dimensional profile of total human τ (hTau) in TC (top) and TH (bottom) animals showing an increase in τ acidic species in the TH animals (arrow). B: SDS-PAGE analysis of τ phosphorylation in TC and TH animals using antibodies targeting physiological (pThr181, pSer214, pThr231, pSer262, pSer396, and pSer404) and pathological (pThr212/Ser214 and pSer422) epitopes. As shown in the left panel, significant enhancement of τ phosphorylation at Ser214, Ser404, and Ser422 was observed in TH mice. This occurred in absence of change in total hTau expression or τ proteolysis (Trunc. Tau). Quantifications of phosphoepitopes were performed vs. total hTau. hTau quantification was performed vs. β-actin. Results are expressed as percentage of TC animals. C: Immunohistochemical analyses of hippocampal τ phosphorylation at pSer202/Thr205 (top left) and pSer422 (bottom left). Scale bar, 500 μm. Results are expressed as means ± SEM. °P < 0.05, °°P < 0.01 vs. TC using Student t test (n = 5–7/group). Black bars, TC; black dashed bars, TH. pI, isoelectric point.

FIG. 4.

Impact of HFD feeding on hippocampal τ kinases and insulin signaling in THY-Tau22 mice. SDS-PAGE analysis was performed using antibodies raised against total and phosphorylated forms of several τ kinases (A) or several components of insulin signaling (B). Results indicate a significant activation of Akt and CaMKII in TH animals together with an upregulation of insulin signaling. Phosphoepitopes were quantified vs. total form of respective protein. Total expressions were quantified vs. β-actin. Results are expressed as means percentage ± SEM of TC animals. °P < 0.05, °°P < 0.01 vs. TC animals, using Student t test (n = 6 to 7/group). Black bars, TC; black dashed bars, TH. IR, insulin receptor.