The aim of this study is to test the hypothesis that depletion of Caveolin-1 accelerates the Alzheimer?s phenotype in aging and aging-linked comorbidities, such as type 2 diabetes. Caveolin-1 (Cav-1) is the principal component of caveolae, and a critical player in lipid rafts. Cav-1 expression is reduced in aging. Here we show that Cav-1 expression is progressively lost in the brains of two mouse models of type 2 diabetes as a function of age and disease deterioration. Type 2 diabetes is a risk factor for Alzheimer?s disease (AD). We provide evidence that depletion of Cav-1 in these mice results in (1) induction of amyloidogenic proteolysis of amyloid precursor protein (APP) (2) compromised vasculature (3) impaired hippocampal neurogenesis (4) impaired learning and memory (5) compromised transport of insulin into the brain and downregulated expression of insulin receptor. This study will test the hypothesis that depletion of Caveolin-1 in the brain accelerates the AD phenotype by inducing amyloidosis and compromising insulin supply into the brain, leading to cognitive impairments. Using T2DM mouse models and Cav-1 transgenic mice Aim 1 will examine the mechanism by which Cav-1 depletion affects APP metabolism, the development of neuropathology and impaired learning and memory in these mice.
Aim 2 will determine the effect of Cav-1 depletion on insulin transport and uptake.
Aim 3 will determine the effect of Cav-1 depletion on vasculature and hippocampal neurogenesis. Experiments will examine whether reconstitution of Cav-1 in endothelial cells of diabetic mice will rescue cognitive deficits and attenuate neuropathology. This study will establish the role of Cav-1 in the development of AD and determine the therapeutic value of intervention in Cav-1 metabolism.
The mechanism by which aging increases the risk of Alzheimer's disease is not known. This project describes that depletion of Cav?1 in aging and type 2 diabetes accelerates cognitive deterioration and neuropathology, leading to Alzheimer's disease.
