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

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 APP(Delta NL/Delta NL) x PS1(P264L/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 (A beta)). 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 A beta deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, A beta was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major A beta-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 APP(Delta NL) x PS1(P264L) 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 A beta 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.