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High fat diet worsens pathology and impairment in an Alzheimers mouse model, but not by synergistically decreasing cerebral blood flow

By Oliver Bracko, Lindsay K. Vinarcsik, Jean C. Cruz Hernández, Nancy E. Ruiz-Uribe, Mohammad Haft-Javaherian, Kaja Falkenhain, Egle M Ramanauskaite, Muhammad Ali, Aditi Mohapatra, Madisen Swallow, Brendah N. Njiru, Victorine Muse, Stall Catchers contributors, Pietro E. Michelucci, Nozomi Nishimura, Chris B Schaffer

Posted 17 Dec 2019
bioRxiv DOI: 10.1101/2019.12.16.878397

Obesity is linked to increased risk for and severity of Alzheimers disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We showed that non-flowing capillaries, caused by adhered neutrophils, underlie the CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensory-motor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd.

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