Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer’s Disease Stage in APP/PS1 Mice

Aug 29, 2016Journal of Alzheimer's disease : JAD

Brain changes linked to a high-fat diet before symptoms appear in an Alzheimer's mouse model

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Abstract

Mice with a high-fat diet showed a significant increase in amyloid-β plaque formation in the hippocampus at 3 months of age.

The high-fat diet led to a notable decrease in insulin degrading enzyme protein levels, which are involved in amyloid-β metabolism.
Hippocampal levels of PGC-1α, a cofactor related to energy production in cells, were significantly reduced in the high-fat diet group.
No changes were observed in insulin receptor gene expression or tau phosphorylation-related enzymes.
The findings suggest that high-fat diet-induced increases in amyloid-β may lead to early neurodegenerative changes associated with Alzheimer's disease.

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Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.

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Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer’s Disease Stage in APP/PS1 Mice

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