Involvement of Myelin Integrity in Alzheimer's Disease Pathogenesis

This R00 application is directed at furthering the understanding of glial responses in white matter in the context of Alzheimer¡¦s disease (AD). The hypothesis to be tested is that a myelin disruption, in the form of decreased myelin proteolipid protein (PLP), induces a white matter specific microglia/macrophage phenotype that is deleterious for axonal health, and that the white matter specific microglia/macrophage phenotype and associated neuroinflammation contribute to cognitive impairments and traditional AD pathology, namely: AƒÒ plaques and hyper-phosphorylation of the microtubule-associated protein tau (MAPT). Conventionally considered a disease of the CNS gray matter, AD also has pronounced and progressive deterioration of cerebral white matter. Recent evidence suggests that changes in myelin integrity could be an early factor driving AD pathology, through stimulation of inflammatory microglia activation and subsequent axonal damage. Extensive work has been done to understand the glial response in AD gray matter yet very little is known about microglia activation in AD white matter, despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD white matter compared to gray matter. No studies have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression. Our project will fill this gap by using human autopsy tissue and a mouse model that exhibits loss of myelin integrity to test our hypothesis. Our specific aims are: AIM 1: Using quantitative digital pathologic methods, quantify myelin integrity (PLP) immunohistochemistry (IHC)), and microglia / macrophage (IBA1 and CD68 IHC), in post-mortem tissue of individuals across the decades of the human lifespan. Specifically, we have identified 130 cases that span from 20 years old to 90 years old at their time of death, with 10-25 cases identified for each decade of life. AIM 2. Determine if loss of myelin integrity, by mutation in PLP, in APP KI mice will accelerate amyloid beta, phosphorylated MAPT, microglia / macrophage ¡V induced inflammation, and cognitive deficits. This project takes advantage of a strong scientific environment and extensive resources at the University of Kentucky, including the Alzheimer¡¦s Disease Center, clinically well-characterized autopsy cases that span the disease pathology continuum, and renowned scientific expertise.