Defining the Role of CXCR4 in Alzheimer's Disease

Celeste Karch, PhD
Washington University School of Medicine (Saint Louis, MO)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2018349S
Award Type:
Standard
Award Region:
US Midwestern
Celeste Karch, PhD

CXCR4 as a Modifier of Tau Aggregation in Alzheimer's Disease

Summary

Several lines of evidence suggest that inflammation and altered function of the cell types in the brain involved in inflammation, such as microglia, represent an early and critical driver of Alzheimer’s disease (AD). Our group has recently shown that a chemokine receptor type 4 (CXCR4) found in the cell types that mediate inflammation in the brain, such as microglia, contributes to tauopathies, such as progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, and AD. The objective of this study is to begin to determine how CXCR4 drives AD. Together, the findings from this study will define the function of a new gene that increases risk for AD and other tauopathies and will shed light on its role in disease processes.

Details

Changes in the cell types in the brain involved in inflammation, such as microglia, represent an early and critical driver of Alzheimer’s disease (AD). Our group has recently shown that a gene found in the cell types that control inflammation in the brain, such as microglia, contributes to tauopathies such as progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, and AD. The objective of this study is to begin to determine how this gene drives AD. To do this, we will use functional genomics and cell biological approaches in human tissue and stem cell models, and we will target this gene in a mouse model of tauopathy to define the effects of this gene on disease course in vivo. Together, the findings from this study will define the function of a new gene that increases risk for AD and other tauopathies and will shed light on its role in disease processes.

About the Researcher

Celeste Karch, PhD is an assistant professor of psychiatry at Washington University in St Louis. She received her doctoral degree from the University of Florida, where she worked with David Borchelt, PhD, to study the mechanisms by which mutant SOD1 protein aggregates in cell and mouse models of amyotrophic lateral sclerosis. Dr. Karch joined Alison Goate, PhD, at Washington University, as a postdoctoral fellow to examine the mechanisms by which cells release tau and how genetic variability associated with tauopathies influences tau release. Dr. Karch’s laboratory is now focused on understanding the molecular mechanisms underlying Alzheimer's disease and other tauopathies by studying genetic risk variants and disease-causing mutations using novel genomic approaches and stem cell and mouse models.  In addition to the BrightFocus award, Dr. Karch is funded by the National Institutes of Health.

Publications

Karch CM, Kao AW, Karydas A, Onanuga K, Martinez R, Argouarch A, Wang C, Huang C, Sohn PD, Bowles KR, Spina S, Silva MC, Marsh JA, Hsu S, Pugh DA, Ghoshal N, Norton J, Huang Y, Lee SE, Seeley WW, Theofilas P, Grinberg LT, Moreno F, McIlroy K, Boeve BF, Cairns NJ, Crary JF, Haggarty SJ, Ichida JK, Kosik KS, Miller BL, Gan L, Goate AM, Temple S; Tau Consortium Stem Cell Group. A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies. Stem Cell Reports. 2019 Oct 4. pii: S2213-6711(19)30335-2. doi: 10.1016/j.stemcr.2019.09.006. [Epub ahead of print] PubMed PMID: 31631020 PubMed Icon Google Scholar Icon

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