The interactions of beta amyloid (Abeta) with microglia and endothelial cells in the brains of patients with Alzheimer?s disease (AD) are mediated by specific receptors for Abeta and may play critical roles in the pathogenesis of AD. Microglia are activated by Abeta to produce proinflammatory cytokines and neurotoxins. Abeta-induced cytokines participate in AD pathogenesis by increasing neurotoxin production and up-regulating the expression and activities of the enzymes that promote Abeta formation such as beta and gamma secretase. Endothelial cell binding to Abeta leads to vascular dysfunction and promotes transport of circulating Abeta and its accumulation into the brain. For these reasons, blocking the interactions of Abeta with its cellular receptors is a potential therapeutic strategy for AD. We identified CD36 as a key receptor that mediates cellular interactions of microglia and endothelial cells with Abeta. To determine the exact role of CD36-Abeta interactions in the pathogenesis of AD, we bred CD36-/- mice with PS1-APP double transgenic mice that develop accelerated AD-like pathology. Analysis of the resulting PS1-APP-CD36-/- mice showed that they have a significant reduction in the level of Abeta in their brain when compared to age matched PS1-APP mice with normal CD36 expression. The decrease in Abeta levels in the brains of PS1- APP-CD36-/- mice was associated with a significant reduction in the number of senile-like plaques, and in the inflammtory response associated with these plaques, suggesting that CD36 expression and/or CD36-Abeta interactions regulate Abeta accumulation and the subsequent development of AD-like pathology in these mice. The overall goal of this grant is to identify the mechanism(s) by which CD36 regulates intracerebral Abeta levels in PS1-APP mice. Accumulation of Abeta in the brain is regulated by three pathways, enzymes that generate Abeta, enzymes that degrade Abeta, and the influx/efflux of Abeta across the endothelium and the blood brain barrier. We will determine the role of CD36 in each of these 3 pathways. We will also determine if restoring the CD36-mediated inflammatory response by repopulating the brain of PS1-APP-CD36-/- with CD36+/+ microglia using bone marrow tranplant from CD36+/+ mice will restore AD-like pathology in these mice. The data obtained from these experiments will help decipher this novel CD36-dependent pathway for regulation of intracerebral Abeta levels. Since CD36 expression in human brains correlates with Abeta levels and since CD36 targeted therapeutics are being explored for diseases other than AD, these experiments will also help us determine if targeting CD36 can be used as a disease modifying therapeutic strategy to stop or delay progression of AD.
Effective and safe therapies for Alzheimer?s disease remain elusive. Understanding how CD36 deficiency protects from Alzheimer?s-like disease in mice, is an important and key first step that will allow us to design CD36 targeted therapies that will stop or delay the progression of this devastating disease and therefore help limit its significant health and economic impact on afflicted individuals, their families and society.
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