Understanding the Role of the Immune System in Frontotemporal Dementia

About the Research Project
Program
Award Type
Postdoctoral Fellowship
Award Amount
$200,000
Active Dates
July 01, 2021 - December 31, 2023
Grant ID
A2021017F
Mentor(s)
Malu Tansey, PhD, University of Florida
Goals
This project aims to understand the role of the peripheral immune system and lysosomal dysfunction in Frontotemporal Dementia FTD. Specific aim 1: Determine the requirement of infiltrating immune cells into the brain in FTD. Using mouse models of FTD, I will determine if dysfunctional immune cells in the periphery are responsible for the neurodegeneration seen in FTD, and if this can be reversed by replacing these with healthy immune cells. Specific aim 2: Assess immune and lysosome dysfunction in immune cells from FTD patients and determine role of the GPNMB protein in this. Lysosomes are cellular organelles that play a role in regulating the immune response. Progranulin, a protein implicated in FTD, regulates lysosomes.
Summary
Understanding the factors responsible for Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) is critical for the development of therapeutic strategies for these debilitating neurodegenerative diseases. Mutations in the GRN gene lead to decreased progranulin protein expression and the development of FTD. It has been suggested that microglia, the resident immune cells of the brain responsible for removing damaged neurons, are hyperactivated and prune healthy neurons, leading to their degeneration. However, evidence previously generated in our lab suggests that microglia are not the only culprit in FTD, but rather immune cells normally found in circulating blood, monocytes, infiltrate into the brain and may play a role in their demise. Lysosomes, organelles in cells responsible for protein recycling and cell signaling, are crucial for proper immune cell function, and may be dysregulated in FTD monocytes. By using a combination of mouse models and FTD-patient samples, this research aims to unveil the role of these peripheral immune cells and dysfunctional lysosomes in the development of FTD.
Unique and Innovative
The completion of proposed studies will provide a clearer understanding of the mechanisms underlying the role of the peripheral immune system in FTD and will inform rational design of new therapies.
Foreseeable Benefits
If the peripheral immune system is instrumental in the aetiology of FTD, it may represent viable therapeutic targets that are in the periphery and therefore more easily accessible than those in the brain, thereby changing the landscape to improve future therapies for patients.
Grants
Related Grants
Alzheimer's Disease Research
The Role of DYRK1A in Altered Microglia Biology in a Cellular Model of Alzheimer’s Disease in Down Syndrome
Active Dates
January 01, 2025 - December 31, 2027
Principal Investigator
Frances Wiseman, PhD
The Role of DYRK1A in Altered Microglia Biology in a Cellular Model of Alzheimer’s Disease in Down Syndrome
Active Dates
January 01, 2025 - December 31, 2027

Principal Investigator
Frances Wiseman, PhD
Alzheimer's Disease Research
Dysregulated Astrocyte p38, Brain Inflammation, and Alzheimer's Pathology
Active Dates
July 01, 2024 - June 30, 2027
Principal Investigator
Linda Van Eldik, PhD
Dysregulated Astrocyte p38, Brain Inflammation, and Alzheimer's Pathology
Active Dates
July 01, 2024 - June 30, 2027

Principal Investigator
Linda Van Eldik, PhD
Alzheimer's Disease Research
Regulation of Microglia Phenotypes in Alzheimer’s Disease
Active Dates
July 01, 2024 - June 30, 2027
Principal Investigator
Johannes Schlachetzki, MD
Regulation of Microglia Phenotypes in Alzheimer’s Disease
Active Dates
July 01, 2024 - June 30, 2027

Principal Investigator
Johannes Schlachetzki, MD