Apolipoprotein E Regulation of Alpha-Synuclein Spreading and Functional Connectivity in Parkinson's Disease Dementia
Abstract
Parkinson disease (PD) is characterized by accumulation of protein aggregates composed of the protein alpha-synuclein (aSyn) in structures termed Lewy bodies (LB) and Lewy neurites (LN) in multiple brain regions. Although motor symptoms are often the most visible features of the illness and are thought to relate to abnormalities in nigro-striatal dopaminergic signaling, PD also causes dementia with prominent cognitive and psychiatric symptoms in many patients. The molecular and circuitry mechanisms that lead to PD dementia are not clear, and there are no effective treatments to prevent or slow progression of dementia in PD. Multiple studies indicate that pathological aSyn aggregation plays a key role in PD, and a growing number of reports now demonstrate that aSyn spreading can be modeled in vivo by stereotaxic injection of aSyn preformed fibrils (PFFs) into the striatum where it then spreads in a time-dependent manner to multiple connected regions including the substantia nigra as well as the cortex and amygdala. Genetic association studies implicate the apolipoprotein E (APOE) genotype as a strong risk factor for dementia in PD. Our preliminary data indicates that apoE isoforms directly regulate aSyn spreading within the nigro-striatal circuit, but whether APOE genotype affects aSyn spreading in neocortical and limbic regions, and whether this contributes to deficits in cognitive behavior and disruption of function connectivity in brain networks is unknown. Hypothesis: APOE4 potentiates aSyn spreading to cortical and limbic regions, disrupting functional.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1195583
Entities
People
- Albert A Davis
Organizations
- Washington University in St. Louis