Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction. Classic neuropathological features of the disease include the formation of extracellular amyloid plaques, intraneuronal deposition of abnormally phosphorylated and aggregated tau protein into neurofibrillary tangles, and gliosis. Glial pathology has generally been considered a secondary, or reactive, change. However, recent advances in understanding normal and pathological glial biology have instead suggested that glia may play an active role in neurological disorders, including Alzheimer's disease. Here we take a genetic approach to define proteins and pathways mediating the influence of glia on Alzheimer's-associated neurodegeneration. Taking advantage of the advanced molecular and genetic tools, short lifespan, and conserved glial biology in Drosophila we will identify glial proteins and pathways that can influence tau neurotoxicity in aging adult brains. In proof of principle studies we validate a novel system for studying non-cell autonomous neurodegeneration in tauopathy. In addition, based on the observation that many genes implicated in Alzheimer's disease through genome wide genetic association studies are expressed predominantly or substantially in glial cells, we will test the effect of upregulating and downregulating these genes in fly glia on tau-induced neurotoxicity. These studies will develop a novel methodology for studying the effect of glia on the neurodegeneration associated with Alzheimer's disease and will ultimately expand the array of molecular and cellular targets relevant for therapy development in this common and devastating disorder.

Public Health Relevance

The proposed studies will capitalize on the strengths of fruit flies as a fast, cheap model system to decipher the molecular pathways in glial cells controlling neurotoxicity in Alzheimer's disease using innovative genetic approaches. These studies will help us design better therapies for Alzheimer's disease and related neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG058275-02
Application #
9735018
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Dibattista, Amanda
Project Start
2018-07-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115