Brain-Invading Monocytes at the Intersection of Alzheimer's Disease and Seizures

Nicholas Varvel, PhD
Emory University (Atlanta, GA)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019077S
Award Type:
Standard
Award Region:
US Southern
Nicholas Varvel

Seizures Promote Alzheimer’s Disease Pathology Via Monocytes

Summary

Alzheimer's disease is and will continue to be a major health problem in the coming decades.  In addition to memory loss, a certain subset of those with Alzheimer's disease also suffer from seizures.  We have recently identified a immune cell type, called a monocyte, that enters the brain after seizures.  The studies are designed to determine seizure-induced monocyte entry into the brain enhances the progression of Alzheimer's disease.

Details

The goal of my project is to identify brain-invading monocytes as a key link between seizure activity and enhanced Alzheimer's disease (AD)-related phenotypes.  In Aim 1, my team and I will determine if seizures exacerbate AD pathology and hasten neurobehavioral decline my inducing seizures in the 5xFAD mouse model of AD.  The resultant alternations in amyloid-beta pathology, and phosphorylated tau levels, immune and neuronal cell numbers, induction of inflammatory meditators, and mouse behavioral will be assessed.  In Aim 2, we will test the hypothesis that brain-invading monocytes enhanced AD pathology in the absence of seizure.  Monocyte brain invasion will be provoked in 5xFAD mice by administering CCL2 into the lateral ventricle.  Then, monocyte infiltration will be blocked via global Ccr2 knockout or CCR2 antagonism in the 5xFAD mice after seizure activity.  As in Aim 1, mouse behavior and brain histological examination will be performed.  If our hypothesis is correct, AD pathologies and behavioral abnormalities will be exacerbated by seizure activity and monocyte brain entry.  Moreover, monocyte brain entry in the absence of seizure will be sufficient to also exacerbate AD pathologies and hasten behavioral decline.  Success in identifying brain-infiltrating monocytes as exacerbating neuroinflammation and cerebral amyloidosis in the AD brain and hastening cognitive decline would an innovative and important step in understanding how seizure activity contributes to AD pathogenesis. The proposed studies will determine if seizure-induced monocyte brain invasion, and not other consequences of seizures, drives AD pathogenesis, an innovative concept.  Evidence that monocyte brain recruitment can be limited after seizures with a CCR2 antagonist and provide disease modification would be groundbreaking.  If this project is successful, we will have identified novel molecular and cellular targets for alleviating the pathological hallmarks of Alzheimer’s disease and modifying disease progression.  Specifically, anti-convulsive medications could be administered to those patients suffering from AD and displaying seizure activity.  In addition, success in determining that brain-invading CCR2+ monocytes accelerate AD progression would support future proof of concept AD clinical trials utilizing CCR2 antagonists previously developed and tested in clinical trials for pancreatic cancer and diabetic nephropathy.

About the Researcher

My long-term scientific goals are to investigate and better understand neuroinflammatory responses in the diseased brain. I hope to achieve these goals by utilizing genetic mouse models, coupled with immunohistological, biochemical, cellular, behavioral, and gene induction analyses. I am interested in the context by which activation and recruitment of myeloid cell subsets are beneficial or harmful after acute injury and chronic neurological disease. My academic training and research experiences have provided me with an excellent background to approach these issues.  As a predoctoral student, I gained invaluable knowledge in mouse genetics by utilizing transgenic mouse models of Alzheimer’s disease (AD) to investigate the underlying causes of abnormal neuronal cell cycle entry and neuroinflammation, events common in AD as well as other neurodegenerative diseases.  For my initial postdoctoral training, I secured funding from the Alexander von Humboldt Foundation to perform neuropathological research in Germany. During my time in Germany, I continued to gain experience working with transgenic mouse models.  I also become competent in stereotaxic surgery and unbiased stereological quantification of stained brain tissue sections.  My research in Tuebingen investigated the potential for circulating monocytes to functionally replace brain-resident microglia in the healthy and diseased brain.  While in the Jucker laboratory, I also developed a chemoconvulsant model of epilepsy to track monocyte infiltration into the brain after seizures. In efforts to apply my knowledge of microglia/monocyte biology to study the role of myeloid cells after seizures, I joined the laboratory of Dr. Raymond Dingledine in June 2013 because of the laboratory’s interest and expertise in therapeutically targeting the neuroimmune system.  My recent work has identified brain-invading monocytes as a driver of neurodegeneration, neuroinflammation, blood-brain barrier erosion, and morbidity after seizure activity.  Given my previous experiences and expertise in AD and seizure mouse models, I am in a unique position to examine the consequences of seizure activity on amyloid burden, neuroinflammation, and behavioral decline.

Personal Story

I would like to thank the BrightFocus donors for their continued support of scientific research.  Your generous contributions to the BrightFocus Foundation make it possible for neuroscientists, like myself, to test new and exciting ideas with the ultimate goal of developing treatments for Alzheimer's disease.

THANK YOU!  

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