Involvement of myelin integrity in Alzheimer's disease pathogenesis

Alzheimer’s disease (AD) requires an extended period of degeneration before the signs of cognitive impairment are evident. Conventionally considered a disease of the CNS gray matter, AD has pronounced and progressive deterioration of cerebral white matter. Many mechanisms have been proposed to underlie the deterioration from cognitively healthy to severe cognitive impairment. One such mechanism, supported by substantial evidence from both clinical studies and preclinical animal models, is a dysregulated glial activation and overproduction of proinflammatory cytokines. In response to activating stimuli or a loss of inhibiting stimuli, microglia and astrocytes halt homeostatic functions and start a self-propagating inflammatory cycle, which contributes to pathophysiological progression of chronic neurodegenerative disorders. Extensive work has been done to understand the glial response in gray matter. Yet, at least in the context of AD, very little is known about microglia activation in white matter despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD brain white matter compared to gray matter. Indeed, intriguing gene array studies from post-mortem samples have shown white matter inflammatory responses occurring early in the disease process, when not yet found in AD gray matter. However, the factors that are causing the inflammatory response have not been defined. The gene array studies also show activation of myelination pathways and lipid transport in the white matter, leading to the prediction of re-myelination, as the molecular pathways activated in early disease are important for the removal of myelin debris and the generation of new myelin. No studies to date have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression to test this hypothesis. To this end we have outlined two specific AIMs. AIM 1: Quantify the relationship between myelin integrity, microglia activation, proinflammatory cytokine levels, and traditional measures of AD burden (NPs and NFTs) from the superior and middle temporal gyri (SMT) and the frontal cortex (FCX) in the white matter of autopsy samples. AIM 2. Determine if loss of myelin integrity, induced by mutation in PLP, in hTau mice will accelerate hyperphosphorylated tau pathology, and if this pathology can be rescued by suppressing the chronic neuroinflammation using a glia cytokine inhibitor. By using the strength of the large number of clinically wellcharacterized autopsy cases available in the brain bank at the University of Kentucky Alzheimer’s Disease Center (UK ADC), we will begin to assess white matter changes in the pathogenesis of AD. Through the development of our preclinical animal model we will be able to address mechanistic questions concerning the role of inflammation following loss of myelin integrity and if the inflammation could mediate hyperphosphorylation of tau. We hope by enhancing our understanding of white matter changes in AD we may develop a new avenue for the development of AD prevention strategies.