Abstract
Most Alzheimer disease (AD) patients present as sporadic late onset AD, with metabolic factors playing an important role in the occurrence and development of AD. Given the link between peripheral insulin resistance and tau pathology in streptozotocin-injected and db/db mouse models of diabetes, we fed high fat diet (HFD) to pR5 mice expressing P301L mutant human tau, with the aim of developing a new model with characteristics of obesity, T2DM and AD to mimic AD patients exacerbated by obesity and T2DM, an increasing trend in modern society. In our study, pR5 and C57BL/6 (WT) mice were randomly allocated to a standard diet (STD) or HFD for 30 weeks starting at 8 weeks of age. Food intake was measured weekly, body weight and fasting glucose levels were measured fortnightly, and a comprehensive behavioral test battery was performed to assess anxiety, depression and cognitive dysfunction. Glucose and insulin tolerance tests were performed after 30 weeks of HFD. We also investigated the effect of long term HFD on tau pathology in the brains of WT and P301L mice by performing western blotting of whole brain homogenates for total tau, phosphorylated tau at Ser396 and Thr231. Our results show that pR5 mice fed with HFD are more vulnerable to diet induced obesity compared to WT, especially with increasing age. In addition, pR5 mice on HFD developed glucose intolerance and insulin resistance. It was identified that long term HFD significantly aggravates depression like behavior and impairs cognitive function in pR5 mice, and also induces anxiety like behavior in both pR5 and WT mice. Long term HFD was also shown to aggravate tau hyperphosphorylation in pR5 transgenic mice, and increase total and hyperphosphorylated tau in WT mice. These results indicate that diet induced obesity of pR5 transgenic mice expressing P301L mutant human tau generates T2DM, and aggravates tau phosphorylation, and is therefore a model useful for investigations that seek to understand the relationships between AD, T2DM and obesity, and the underlying biochemical changes and mechanisms associated with metabolic disorders and AD tauopathy.
Highlights
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HFD induced obesity of pR5 transgenic mice expressing P301L mutant human tau generates T2DM.
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HFD induces glucose intolerance and insulin resistance in pR5 mice.
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pR5 mice are more vulnerable to HFD induced obesity compared to WT especially with increasing age.
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pR5 mice are more vulnerable to HFD induced glucose intolerance impairment compared to WT especially with increasing age.
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Long term HFD significantly aggravates depression like behavior and cognitive deficit in pR5 mice.
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Long term HFD aggravates tau hyperphosphorylation in pR5 transgenic mice.
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Data availability
The authors declare that data will be made available upon reasonable request.
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Acknowledgements
We thank and acknowledge Dr. Mohammed Al-Hawwas for training and help with mouse genotyping.
All authors critically reviewed content and approved final version for publication.
Funding
This work was supported by grants from NHMRC APP1020567, Chinese CSC 2011CB944200, Discipline leader program of Yunnan Province D-2017028 and Research program of Health Commission of Yunnan Province 2017NS287.
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Xin-Fu Zhou was responsible for the study concept and design. Jing Xiong contributed to the animal work, data analysis and interpretation of findings. Issac Deng, Sally Kelliny, and Liying Lin assisted with animal work. Jing Xiong drafted the manuscript, Xin-Fu Zhou provided critical revision of the manuscript and Larisa Bobrovskaya supervised students involved.
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Xiong, J., Deng, I., Kelliny, S. et al. Long term high fat diet induces metabolic disorders and aggravates behavioral disorders and cognitive deficits in MAPT P301L transgenic mice. Metab Brain Dis 37, 1941–1957 (2022). https://doi.org/10.1007/s11011-022-01029-x
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DOI: https://doi.org/10.1007/s11011-022-01029-x