Alzheimer's disease (AD) is associated with activation of microglia in the vicinity of amyloid plaques with both detrimental results due to release of neurotoxic and pro-inflammatory mediators and beneficial effects due to amyloid phagocytosis. It is increasingly recognized that compared to normal aging, AD is associated with impairment of both innate and adaptive arms of the immune system. As key innate immune cells, microglial senescence may contribute to the development or progression of neurodegenerative diseases. Peripheral macrophages and microglia can adopt different stimulus-dependent activation states, termed classical and alternative activation, with different associated functions. Little is known about the contribution of these different microglial activation states to AD pathogenesis and disease course. This proposal will test the hypothesis that microglial activation patterns and phenotypes are differentially affected in healthy and pathological aging and contribute to impaired amyloid phagocytosis In AD. We will first establish a microarray gene signature for classical and alternative activation states by exposing cultured postmortem human microglial cells to appropriate cytokine stimuli. Using flow cytometry, real-time PCR and immunohistochemical techniques, we will then compare the activation pattern and potential of microglia derived from aged patients with no AD pathology, mild AD pathology but no dementia and from demented AD patients. We expect to see no differences in classical activation potential but an age- and disease-dependent decline in alternative activation. Lastly, we will evaluate activation-state dependent functional differences between these patient groups by performing amyloid phagocytosis assays, and measuring the release of chemokines, cytokines and neurotrophic factors. Together these studies will contribute to our understanding of distinct microglial functions and activation patterns, will begin to elucidate the degree to which microglia from aged and diseased brain are amenable to cytokine stimulation in vitro and will point to potential therapeutic means of modulating microglial phenotype in vivo.

Public Health Relevance

Microglia have a central role in the pathogenesis of Alzheimer's disease and have become a promising therapeutic target. While global suppression of microglial activation may not be beneficial, selective suppression or stimulation may. This proposal will assess distinct microglial functions and activation patterns and will begin to elucidate how to selectively modulate the innate immune response in the brain as a means to prevent pathological aging and/or modify the course of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005133-30
Application #
8449135
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
30
Fiscal Year
2013
Total Cost
$168,678
Indirect Cost
$57,559
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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