Grants and Contracts Details
Description
Loss of physiological microglia function is now believed to contribute to the development of Alzheimer’s
disease. Dystrophic microglia are now known to be a common feature of AD, and thus necessitate mechanistic
exploration of this poorly defined glia pathology. Successful completion of this project will lead to the discovery
of a novel target, in microglia iron homeostasis, to restore the healthy function of microglia, and prevent the
degeneration of these cells.
Evidence from genetic, biochemical, and neuropathological studies has shown that loss of homeostatic
microglia function contributes to Alzheimer’s disease (AD) pathogenesis. From our work and the work of
others, dystrophic microglia are now known to be a common feature of AD and other neurodegenerative
diseases, but little is known about the causes and consequences of dystrophic microglia in AD. Our pilot data
from an unbiased proteomic screening of AD brains has identified ferritin light chain (FTL) as a top candidate
protein. FTL is used to store excess iron in microglia. Prior studies have shown that dystrophic microglia in the
AD brain express high amounts of ferritin. Regulation of iron homeostasis occurs by the influx, storage, and
efflux of iron from cells. Our project is a departure from prior work on microglia in AD, as we will define the
mechanisms leading to a primary glial pathology. Our hypothesis that dysregulation of iron homeostasis is a
driving force in microglial degeneration is novel. Moreover, the current evidence suggests that dystrophic
microglia is a human-specific glia pathology seen following advance age, and is generally not seen in diseaserelevant
animal models. By using complementary histological, biochemical, and flow cytometry methods in
human brain tissue, we will define this human-specific glia degeneration. We hypothesize that a
dysregulation of iron homeostasis is a driver of dystrophic microglia in neurodegenerative disease.
Using biosamples from the University of Kentucky Alzheimer’s Disease Center biobank of well-characterized
tissue encompassing the full spectrum of disease severity, we will address the following specific aims:
Aim 1: Define the iron influx pathway in dystrophic microglia
Aim 2: Define iron storage pathway in dystrophic microglia
Aim 3: Define iron efflux pathway in dystrophic microglia
Overall impact: This project will lead to the discovery of a novel target, in microglia iron homeostasis, to restore
the healthy function of microglia, and prevent the degeneration of these cells.
Status | Finished |
---|---|
Effective start/end date | 5/1/20 → 4/30/23 |
Funding
- National Institute on Aging: $420,750.00
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