Aging and high-fat diet feeding lead to peripheral insulin resistance and sex-dependent changes in brain of mouse model of tau pathology THY-Tau22

0543849 - FGÚ 2022 RIV GB eng J - Journal Article
Kacířová, M. - Železná, B. - Blažková, M. - Holubová, M. - Popelová, A. - Kuneš, Jaroslav - Šedivá, B. - Maletínská, L.
Aging and high-fat diet feeding lead to peripheral insulin resistance and sex-dependent changes in brain of mouse model of tau pathology THY-Tau22.
Journal of Neuroinflammation. Roč. 18, č. 1 (2021), č. článku 141. E-ISSN 1742-2094
R&D Projects: GA ČR(CZ) GA20-00546S; GA MŠMT(CZ) ED1.1.00/02.0109
Research Infrastructure: CCP II - 90126
Institutional support: RVO:67985823
Keywords : Alzheimer’s disease * THY-Tau22 mouse * obesity * neuroinflammation * peripheral insulin resistence * sex differences
OECD category: Physiology (including cytology)
Impact factor: 9.589, year: 2021
Method of publishing: Open access
https://doi.org/10.1186/s12974-021-02190-3

Background Obesity 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. Methods Three-, 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. Results Increased 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. Conclusions Significant 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.
Permanent Link: http://hdl.handle.net/11104/0320965