Role of MyD88 signaling in systemic inflammation and Alzheimer disease

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Project Summary / Abstract The main pathological changes found in patients with Alzheimer’s disease (AD) are extracellular amyloid β (Aβ) deposits in the brain parenchyma (amyloid plaques) and abnormal aggregates of hyperphosphorylated tau protein in brain neurons (neurofibrillary tangles, NFTs). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased levels of cytokines. Except a small subset of early-onset familial AD cases, the causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular mechanisms that increase the risk for the vast majority of AD cases and to develop the preventive and therapeutic measures. Systemic inflammation promotes AD progression and even initiates microglial activation and neurodegeneration. Indeed, recent genetic studies on late-onset AD have identified about a dozen genetic risk variants that are highly expressed in microglia and involved in innate immune responses, highlighting the importance of immune responses, particularly activated microglia, in the pathogenesis of late-onset AD. Aging is the largest known risk factor for AD and is characterized by chronic, systemic inflammation (inflamm-aging). Systemic inflammation caused by certain bacterial and viral infections is a strong risk factor of dementia, also. Additionally, our preliminary data indicate that activation of NLRP3 inflammasome through the MyD88 signaling pathway in microglia in the central nervous system (CNS) plays essential roles in the AD pathogenesis. In Aim 1, we will produce a microglia specific MyD88 deficiency in AD mouse models during aging and determine their effect on Aβ and tau pathology and cognitive function. We further hypothesize that microglial MyD88 signaling plays a predominant role in accelerating brain Aβ and tau pathology and neuroinflammation, which are induced by chronic, systemic inflammation, in AD mouse models during aging. In Aim 2, we will determine the effects of systemic LPS treatment on Aβ and tau pathology and cognition in AD mouse models with brain and peripheral immune cell-specific MyD88 deficiency. In Aim 3, we will determine the age and sex dependent effects of LPS treatment on NLRP3 inflammasome activation as disease mechanisms in the brain/microglia-specific and peripheral immune cell-specific MyD88 deficient AD mouse models. Our hypothesis is that LPS-induced systemic inflammation causes NLRP3 inflammasome activation in microglia via MyD88 signaling, leading to exacerbation of AD-like pathophysiology in AD mouse models. The long term goals are to determine the role of microglial MyD88/NLRP3 inflammasome signaling in the AD pathogenesis, to elucidate the molecular mechanism underlying the increased AD risk associated with systemic inflammation and to develop new preventive and therapeutic strategies for AD.