Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily spread to cortical and subcortical structures and lead to isolated behavioral symptoms

Abstract

Parkinson's disease dementia (PDD) and Lewy Body dementia (LBD) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. These patients have a neuropsychological pattern of deficits that include executive dysfunction, including 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 LBD and PDD. To investigate the consequences of α-syn pathology in the cortex, we injected human α-syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced α-syn deposition in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or working memory but did mildly alter behavioral flexibility as measured by reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology adds to our understanding of the etiology of varied symptoms in PDD and LBD.