Diabetes, Alzheimer's Disease and Exercise Intervention

Chronic Type 2 Diabetes Mellitus (T2DM) is associated with a multitude of secondary complications, including vascular disease, dementia, and stroke. In addition, T2DM confers an increased risk for Alzheimer’s Disease (AD), through undetermined and likely complex, mechanisms. There is evidence that AD patients with T2DM display a shift from parenchymal to vascular amyloid deposition, potentially destabilizing the vascular wall and triggering changes in vascular permeability, microhemorrhages, and mini-strokes. These detrimental changes to cerebrovascular health are likely unique to T2DM patients and would compound AD-related dementia. In order to investigate the impact of T2DM on AD pathology, we have created a novel mouse model that recapitulates features of both diseases. The line of knock-in mice (Leprdb/db x APPÄNLh/ÄNLh x PS1P264L/P264L; db/AD) become rapidly obese and diabetic, and develop AD-related neuropathology. Our preliminary data suggests that AD-related mutations increase the incidence of cerebral aneurysms and that the confluence of T2DM and AD-related mutations significantly increases the incidence of stroke in aged animals. Our central hypothesis is that T2DM lowers the threshold for stroke in animals with AD-related vascular pathology. To address this hypothesis, we propose to modify cerebrovascular pathology and stroke incidence through the use of exercise. To this end, we will use mild-to-moderate involuntary exercise in middle-aged mice and use the following outcomes to determine the effect on cerebrovascular health: 1. MRI. We will use MRI to quantify the incidence and onset of stroke and other vascular events. 2. Vascular Corrosion Casting/Scanning Electron Microscopy. We will examine the effect of exercise on the incidence of aneurysms and vascular density and destabilization by SEM. The major strength of this proposal is our unique mouse model.