Does the APOE Gene Regulate Protein Aggregation in PD?

Albert Davis, MD, PhD
Washington University School of Medicine (St. Louis, MO)

Mentors

David Holtzman, MD
Washington University (St. Louis, MO)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2017
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2015577F
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern
Albert Davis, MD, PhD

ApoE Regulation of Alpha-Synuclein Pathology

Summary

In several brain disorders, including both Alzheimer disease (AD) and Parkinson disease (PD), certain proteins aggregate, or become clumped, in a way that is harmful to the brain. The factors that influence the clumping of these proteins are not completely known. We believe that a variation in the APOE gene, one that is strongly linked to increased risk of AD, may also influence protein clumping and neurodegeneration in PD. This project will study how brain proteins clump and will hopefully pave the way for new treatments for brain diseases including AD, PD, and related brain disorders.

Details

Synucleinopathies including Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized pathologically by neurodegeneration and aggregation of the protein alpha-synuclein (αSyn).  Patients with these diseases develop parkinsonism (movement problems) but also develop cognitive problems similar to those in Alzheimer disease (AD).  The mechanisms that influence αSyn aggregation are unclear.  APOE is the strongest genetic risk factor for AD, and there is very strong evidence that one of the main effects of the APOE gene in AD occurs via metabolism of Aβ, a protein fragment which becomes aggregated in the brain in AD. Several lines of evidence now suggest that apoE isoforms may regulate αSyn aggregation as well. Our central hypothesis is that apoE isoforms regulate the uptake and seeding of αSyn and thereby influence the development of synuclein pathology which contributes to dementia.. We hope that this work will increase our understanding of the role that APOE plays in diseases marked by synuclein aggregation and dementia.

About the Researcher

Albert (Gus) Davis, MD, PhD, graduated with highest honors from Emory University in 2002, then enrolled in the Medical Scientist Training Program at Emory University where he earned his PhD in neuroscience in 2009. He completed his medical training at Vanderbilt University where he earned his MD in 2011.  After an internship in Internal Medicine, Dr. Davis completed his neurology residency at Washington University and Barnes-Jewish Hospital in 2015, serving as an administrative chief resident in his final year. Following residency training, he remained at Washington University for postdoctoral scientific training in the laboratory of David Holtzman, MD, as well as clinical training in Movement Disorders.



"I began working in the Alzheimer disease (AD) field in graduate school and remained interested in AD and related diseases during medical school and my neurology residency, in large part thanks to the passion and expertise of my clinical and scientific mentors. I am extremely grateful to have research support from the BrightFocus Foundation and its generous donors at this early stage in my career. I am hopeful that the near future will bring new advances in the understanding of disease mechanisms, diagnostic tools, and therapies for AD, and am excited to contribute to these ongoing efforts to combat this devastating disease."

Publications

Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD, Miller R, Choudhury FA, Sullivan PM, Cruchaga C, Perlmutter JS, Ulrich JD, Benitez BA, Kotzbauer PT, Holtzman DM. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med. 2020 Feb 5;12(529). pii: eaay3069. doi: 10.1126/scitranslmed.aay3069. PubMed PMID: 32024799. PubMed Icon Google Scholar Icon

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