Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia

Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia

Acta Neuropathologica Communications, June 2014

24916066

Dana M Niedowicz, Valerie L Reeves, Thomas L Platt, Katharina Kohler, Tina L Beckett, David K Powell, Tiffany L Lee, Travis R Sexton, Eun Suk Song, Lawrence D Brewer, Caitlin S Latimer, Susan D Kraner, Kara L Larson, Sabire Ozcan, Christopher M Norris, Louis B Hersh, Nada M Porter, Donna M Wilcock, Michael Paul Murphy

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPDeltaNL/DeltaNL x PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of beta-amyloid (Abeta)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Abeta deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Abeta was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Abeta-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPDeltaNL x PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Abeta deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.