Alpha-Synuclein Pre-Formed Fibrils Injected into Prefrontal Cortex Primarily Spread to Cortical and Subcortical Structures

• Published in: Journal of Parkinson's disease Vol. 14; no. 1; pp. 81 - 94
• Main Authors: Weber, Matthew A., Kerr, Gemma, Thangavel, Ramasamy, Conlon, Mackenzie M., Gumusoglu, Serena B., Gupta, Kalpana, Abdelmotilib, Hisham A., Halhouli, Oday, Zhang, Qiang, Geerling, Joel C., Narayanan, Nandakumar S., Aldridge, Georgina M.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2024; IOS Press BV
• Subjects: alpha-Synuclein - metabolism; Alzheimer Disease; Animals; Brain stem; Cognitive ability; Dementia; Dementia disorders; Executive function; Fibrils; Humans; Lewy bodies; Male; Mesencephalon; Mice; Movement disorders; Neurodegenerative diseases; Parkinson Disease - pathology; Parkinson's disease; Pathology; Prefrontal cortex; Prefrontal Cortex - pathology; Reversal learning; Short term memory; Spatial discrimination learning; Synuclein; behavioral flexibility; exploratory behavior; Prefrontal cortex; alpha-synuclein; Parkinson’s disease
• ISSN: 1877-7171; 1877-718X
• DOI: 10.3233/JPD-230129

Background: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. Objective: To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn. Methods: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions. Results: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. Conclusions: This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.