Role of Microglia in Alzheimer's Disease: Deleterious or Helpful?

Jean-Vianney Haure-Mirande, PhD
Icahn School of Medicine at Mount Sinai (New York, NY)

Mentors

Michelle Ehrlich, MD
Icahn School of Medicine at Mount Sinai
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2016482F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

This grant is made possible by support from the J.T. Tai Foundation.

Jean-Vianney Haure-Mirande, PhD

Role of TYROBP in the Pathogenesis of Alzheimer's Disease

Summary

Recent studies highlight the possible role of the immune system in Alzheimer’s disease (AD). The immune system and its activation can be a “double-edge sword” event in AD: on one hand, it can protect the brain by reducing the formation of amyloid plaque, but on the other hand, it can induce brain inflammation and have deleterious effects. The aim of our project is to: 1) understand the role of the immune system in the pathogenesis of AD, and 2) provide new insight for a therapeutic target to control AD. 

Details

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (Aß) peptide accumulation which is believed to be a major pathophysiologic factor of the disease. An inflammatory component in AD has long been recognized, and it was first assumed that the chronic neuroinflammation associated with AD may be a secondary or even protective event in response to Aß deposition, and may occur only in late stages of AD. Recent genetic studies, however, identified an association between AD and mutations in genes encoding important immune mediators, eg, CD33 [an immunoregulatory receptor] and TREM2 [triggering receptor expressed on myeloid cells 2]. Their discovery highlights the role of a dysregulated immune response and neuroinflammation in AD, and suggests an earlier, and perhaps causative, role in pathogenesis.

In addition, integrative genomic analyses of human AD brain transcriptomes have provided convincing data regarding the role of microglia in the pathogenesis of AD. Microglial activation may be causative, reactive, and/or protective, perhaps varying with disease stage. For example, phagocytosis of Aß peptides may prevent their deposition into plaques. Alternatively, microglial activation leads to the release of proinflammatory cytokines that can contribute to neuronal death.

Using computational analysis, members of our team has identified TYROBP [TYRO protein tyrosine kinase-binding protein] as a causal regulator of multiple genes involved in microglia activation and its expression is increased in AD human and mouse brains.

We have proposed one of the first studies that would allow the validation of a network analysis model in AD. In particular, we will determine how TYROBP modifies and/or regulates the inflammatory response in mice in the presence or absence of mutations that lead to AD. We will perform detailed transcriptomic analysis in microglial cells and two vulnerable brain regions during presymptomatic and symptomatic stages of AD in the presence or absence of TYROBP. The transcriptomic analysis will be corroborated with behavioral tests of cognitive performance in order to assess whether modulation of TYROBP expression and microglia activation can have beneficial effects in AD symptoms.

This study should advance our understanding of the normal function of TYROBP and its role in AD, including its role as a potential therapeutic target. 

About the Researcher

I am a postdoctoral fellow in the Department of Neurology at Icahn School of Medicine at Mount Sinai. Prior to this, I obtained my bachelor’s and master’s of science degrees in molecular biology at the University of Nantes (France). In 2013, I obtained my PhD degree in molecular biology and epigenetic, during which I focused on the study of inflammatory bowel disease and colorectal cancer. I then joined the Immunology Department at Icahn School of Medicine at Mount Sinai to enhance my knowledge of immunology and inflammatory diseases. In 2015, I joined the Department of Neurology to focus and apply my knowledge in immunology to the study of neurological disease. My primary research interest is to study the role of the central nervous immune system during the pathophysiology of Alzheimer’s disease.

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