We have new evidence that glutamate induction of neuronal pAPP expression is regulated in an isoform specific manner by ApoE. We hypothesize that such regulation is an important component of neuronal responses to adverse stimuli and that ApoE is directed toward maintaining pAPP expression in the face of compromised synaptic inputs and of neuroinflammation;failure of this coordination is neuropathogenic. To address this hypothesis, we will employ cell and molecular techniques to define and characterize sequential relationships, genetic modulation, and mechanistic processes in this pAPP-ApoE axis, using tissue from AD and control patients, animal models, and cell cultures. Our three specific aims build upon our preliminary findings relating glutamate and IL-1 to interactions between pAPP and ApoE in cell culture, animal models, and AD.
(Aim 1) Determine the mechanisms through which glutamate-induced ApoE upregulates pAPP. For this, we will use purified neurons, astrocytes, and microglia derived from wild type and various transgenic mice.
(Aim 2) Determine the role of ApoE and its receptors in the modulation of pAPP in proximity to amyloid plaques. The relationship between neuronal expression of pAPP, ApoE, and ApoE receptors relative to plaque density will be determined in cerebral cortical regions of AD and control patients as well as in transgenic mice.
(Aim 3) Define and characterize mechanisms of IL-1 modulation of glutamate induction of the ApoE?pAPP axis. Here we will determine the relationship between glial expression of IL-1 and neuronal expression of pAPP, ApoE, and ApoE receptors relative to plaque density in wild type and transgenic mice. Successful completion of our aims will provide greater understanding of how Apoe genotype is related to AD risk, as well as provide potential targets for development of AD therapeutics.

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National Institute on Aging (NIA)
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University of Arkansas for Medical Sciences
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