Relative Contribution of Central vs. Peripheral Immune Cells in Cerebral Amyloid Beta Clearance

Marie-Victoire Guillot-Sestier, PhD
University of Southern California (Los Angeles, CA)

Mentors

Town Terrence, PhD
University of Southern California (Los Angeles, CA)
Year Awarded:
2015
Grant Duration:
November 1, 2015 to February 1, 2017
Disease:
Alzheimer's Disease
Award Amount:
$99,646
Grant Reference ID:
A2015309F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southwestern
Marie-Victoire Guillot-Sestier, PhD

Amyloid Beta Clearance by Central vs. Peripheral IL-10R-/- Monocytes

Summary

Innate immune cells function to protect the organism against pathogens, and are divided in two groups: a “central” group located in the central nervous system, and a “peripheral” group in the rest of the body.  Alzheimer's disease (AD) is defined in part by the brain’s accumulation of a toxic agent called amyloid beta (Aβ) that destroys neurons and induces memory loss.  We will use mice that develop amyloid plaques to study which group of immune cells−“central” or “peripheral”−are able to clear the brain of toxic Aβ peptides.

Details

The goal of my research is to understand the role of innate immune cells in response to brain accumulation of Aβ, the toxic agent that induces changes resulting in memory loss in AD. Innate immune cells function to protect and clear the organism from pathogens, and are divided in two groups: a “central” group located in the brain, and a “peripheral” group in the rest of the body. During the past decades, neuroscientists have shown that, in the brain of AD patients, immune cells are inefficient at clearing Aβ. My recent findings show that blocking the production of the anti-inflammatory agent IL-10 boosts immune cells to wipe Aβ from the brain of transgenic AD-like mice. Currently, my ambition is to identify whether resident central and/or infiltration of peripheral immune cells in the brain are responsible for Aβ clearance.

The first objective of my project is to obtain, characterize and validate a new experimental mouse model of AD in which we could boost independently the activity of central or peripheral innate immune cells.  This will be achieved using a state-of-the-art breeding strategy between transgenic AD-like mice and genetically engineered mouse models allowing deletion of IL-10 signals specifically in central or peripheral innate immune cell sub-populations.

The second objective is to use these chimeric mice to determine which group of immune cells−central and/or peripheral−is able to clear the brain of toxic Aβ. To this aim, we will test whether boosting each specific subset of innate immune cells --by inhibition of the IL-10 pathway-- increases Aβ uptake by those cells in the brain of AD-like mice. We will also investigate whether neuronal integrity is restored and if learning and memory deficits observed in transgenic AD-like mice are rescued.

One innovative aspect of my project is to use a state-of-the-art mouse genetic engineering and breeding strategy to produce complex chimeric mouse models permitting us to delineate the relative contribution(s) of central vs. peripheral immune cells in the context of AD-like pathology.

The second innovation is our use of cutting-edge tri-dimensional reconstitution of mouse brain sections, using high-resolution microscopy. The exciting new methodology that we developed allows, for the first time, 3D visualization of Aβ “swallowed” by innate immune cells and quantification of effective Aβ clearance directly into mouse brain sections.

There is currently no cure or effective treatment for AD. In past decades, therapeutic strategies aiming at reducing cerebral Aβ production have provoked adverse events in patients. Therefore, a promising alternative approach would be to target the other side of the equation: Aβ clearance. We hypothesize that, if activated appropriately, innate immune cells can be enlisted to clear the brain of Aβ deposits. Upon completion, this project will provide critical data on which specific sub-population of innate immune cells needs to be targeted to induce clearance of Aβ. This will be an initial and major step toward a novel innate immune modulation strategy, in hopes of identifying new therapeutic targets for this devastating disorder of the mind.

About the Researcher

Marie-Victoire Guillot-Sestier, PhD, is a postdoctoral research scholar in the Zilkha Neurogenetic Institute at the University of Southern California. She completed her doctoral studies in cellular and molecular aspects of neurobiology at the University of Nice-Sophia Antipolis (France), where she worked on the production and function of peptides derived from proteins like β amyloid precursor protein (βAPP) and the cellular prion protein (PrPc) involved in neurodegenerative diseases. During this time she exposed a neuroprotective function associated with N1, the soluble N-terminal fragment of the PrPc, and its ability to protect against Aβ toxicity. Three years ago she transitioned to Terrence Town’s laboratory at USC to focus her work on the contribution of immune cells and pathways in the pathoetiology of AD. Her recent work shows that blocking the production of the anti-inflammatory agent IL-10 boosts immune cells to clear β-amyloid from the brain of transgenic AD-like mice. These findings validate the concept that “re-balancing” innate immunity to wipe away toxic plaques from the brain may bring new hope for a safe and effective treatment for AD.



"Alzheimer’s disease is devastating physically, psychologically and emotionally for both patients and their families. It is the public health crisis of our time. I am extremely grateful that the BrightFocus Foundation has awarded my project with their interest and trust. This support, through the generosity of the donors, is fundamental for basic research to evolve, for our knowledge to expand, and for our hopes of curing Alzheimer’s disease to be kept alive.

Finding a cure for Alzheimer’s disease is one of the greatest challenges for a neuroscientist.  I am happy and proud to be contributing my time and energy to the international scientific effort aimed at unraveling the patho-etiology of this disease. Through this proposed project and beyond, I am strongly committed to focusing my career on providing a more detailed picture of the immune mechanisms taking place during the disease process. In the long term, I believe that our findings will help identify new therapeutic targets that assist in developing of a safe and efficient cure."

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