Apolipoprotein E Regulation of Alpha-Synuclein Spreading and Functional Connectivity in Parkinson s Disease Dementia
Abstract
Background: In addition to well-recognized motor symptoms (tremor, slowness, balance problems), Parkinson disease (PD) causes memory and thinking impairment (dementia) in up to 80% of patients who live 15-20 years with PD. The exact cause is not clear, but PD dementia is thought to result from the accumulation of a normal brain protein called alpha-synuclein (aSyn) into abnormal aggregates that are toxic to brain cells. It is known that PD patients who have one version of the apolipoprotein E (APOE) gene called APOE4 are at increased risk of developing dementia. Recent advances in experimental model systems have demonstrated that injection of a small amount, or "seed," of aggregated aSyn protein into a vulnerable region of a normal mouse brain can induce aggregation of the normal mouse aSyn protein, which leads to brain cell death and motor symptoms reminiscent of human PD patients. Our preliminary research indicates that mice that express APOE4 are more susceptible to aSyn spreading in some brain circuits that are important for movement, but it is not clear if APOE4 affects spreading in other brain circuits that are important for thinking and emotion, or whether spreading of aSyn aggregates to these regions will result in disruption of brain network function and lead to behavioral abnormalities. Our hypothesis is that the APOE4 gene will accelerate abnormal aSyn spreading in regions of the brain that are important for thinking and emotion, disrupting brain network function and causing behavioral symptoms. Applicability: The ultimate goal of this research is to understand the molecular mechanisms that contribute to PD dementia so that we can test the role of genes that are thought to protect against or accelerate disease, and to test the efficacy of drugs designed to slow and stop the harmful cascade of brain cell damage in PD. Because PD takes years to develop and progress in humans, it is vital that we first test the role of genetic risk factors and the potential of disease-modifying treatments in model systems that recreate the key features of the disease in months, not years or decades. Because most patients with PD are at risk of eventually developing dementia, this proposed study has the potential to help all patients with PD. If our hypothesis is correct and APOE4 accelerates aSyn spreading and worsens cognitive symptoms, this would suggest that therapeutic strategies to target apoE may be beneficial at least for patients carrying the APOE4 version of the gene, and possibly even for those who do not. This model system may also be useful to test whether disease-modifying therapies are effective for all patients regardless of APOE genotype, or whether patients carrying APOE4 or other genetic risk factors may respond differently to disease-modifying therapies. One risk of this type of research is that the lessons learned in mice may not translate to humans. However, the validity of this model system that has been demonstrated so far, and the urgent need to accelerate the pace of discovery and treatment development, may make this risk acceptable. The model system that will be utilized in the proposed research should allow us to make definitive conclusions about the role of APOE4 in aSyn aggregation and PD dementia within 1-2 years. The likely impact of this study is that we will improve our understanding of the mechanism by which the strongest genetic risk factor for PD dementia contributes to brain cell dysfunction and will improve our understanding of animal model systems for testing disease-modifying therapies. Career goals: My career goal is to formulate relevant questions about Parkinson disease based on clinical observations made while caring for patients, to conduct hypothesis-driven research to better understand disease mechanisms, and to bring disease-modifying treatments to the clinic to improve the quality of life for patients and caregivers. This research plan will support me in achieving these goals by p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010934
Entities
People
- Albert A Davis
Organizations
- United States Army
- Washington University in St. Louis