Abstract
BackgroundObesity leads to low-grade inflammation in the adipose tissue and liver and neuroinflammation in the brain. Obesity-induced insulin resistance (IR) and neuroinflammation seem to intensify neurodegeneration including Alzheimer’s disease. In this study, the impact of high-fat (HF) diet-induced obesity on potential neuroinflammation and peripheral IR was tested separately in males and females of THY-Tau22 mice, a model of tau pathology expressing mutated human tau protein.MethodsThree-, 7-, and 11-month-old THY-Tau22 and wild-type males and females were tested for mobility, anxiety-like behavior, and short-term spatial memory in open-field and Y-maze tests. Plasma insulin, free fatty acid, cholesterol, and leptin were evaluated with commercial assays. Liver was stained with hematoxylin and eosin for histology. Brain sections were 3′,3′-diaminobenzidine (DAB) and/or fluorescently detected for ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and tau phosphorylated at T231 (pTau (T231)), and analyzed. Insulin signaling cascade, pTau, extracellular signal-regulated kinase 1/2 (ERK1/2), and protein phosphatase 2A (PP2A) were quantified by western blotting of hippocampi of 11-month-old mice. Data are mean ± SEM and were subjected to Mann-Whitney t test within age and sex and mixed-effects analysis and Bonferroni’s post hoc test for age comparison.ResultsIncreased age most potently decreased mobility and increased anxiety in all mice. THY-Tau22 males showed impaired short-term spatial memory. HF diet increased body, fat, and liver weights and peripheral IR. HF diet-fed THY-Tau22 males showed massive Iba1+ microgliosis and GFAP+ astrocytosis in the hippocampus and amygdala. Activated astrocytes colocalized with pTau (T231) in THY-Tau22, although no significant difference in hippocampal tau phosphorylation was observed between 11-month-old HF and standard diet-fed THY-Tau22 mice. Eleven-month-old THY-Tau22 females, but not males, on both diets showed decreased synaptic and postsynaptic plasticity.ConclusionsSignificant sex differences in neurodegenerative signs were found in THY-Tau22. Impaired short-term spatial memory was observed in 11-month-old THY-tau22 males but not females, which corresponded to increased neuroinflammation colocalized with pTau(T231) in the hippocampi and amygdalae of THY-Tau22 males. A robust decrease in synaptic and postsynaptic plasticity was observed in 11-month-old females but not males. HF diet caused peripheral but not central IR in mice of both sexes.
Highlights
The prevalence of obesity is increasing worldwide [1], leading to diverse comorbidities and increasing the cost of their cure
Impaired short-term spatial memory was observed in 11-month-old THY-tau22 males but not females, which corresponded to increased neuroinflammation colocalized with Phosphorylated tau protein (pTau)(T231) in the hippocampi and amygdalae of THY-Tau22 males
The present study aims to determine if age-dependent obesity resulting from HF diet feeding causes insulin resistance (IR) in the periphery, affects insulin signaling in the hippocampus, leads to impaired age-related behavioral and memory changes, and worsens neuroinflammation in the brain separately in males and females of THY-Tau22 mice and corresponding wild-type controls
Summary
The prevalence of obesity is increasing worldwide [1], leading to diverse comorbidities and increasing the cost of their cure. Obesity supports low-grade inflammation in the adipose tissue and the liver and neuroinflammation in the hypothalamus [2, 3]. Obesityrelated neuroinflammation has been detected in extrahypothalamic brain structures such as the hippocampus or brain cortex (reviewed by [3, 4]) and linked to impaired cognitive function. Both IR and low-grade neuroinflammation resulting from obesity seem to intensify neurodegenerative changes in brains affected by Alzheimer’s disease (AD) [5]. Obesity leads to low-grade inflammation in the adipose tissue and liver and neuroinflammation in the brain. The impact of high-fat (HF) diet-induced obesity on potential neuroinflammation and peripheral IR was tested separately in males and females of THY-Tau mice, a model of tau pathology expressing mutated human tau protein
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