Intrastriatal injection of amplified Lewy body dementia (LBD) fibrils in mice results in accumulation of fibrils with LBD structure and neurodegeneration

Abstract

The defining neuropathologic feature of Lewy body dementia (LBD) and Parkinson's disease (PD) is alpha-synuclein (Asyn) fibril accumulation in Lewy bodies (LBs) and Lewy neurites (LNs). Recently, we developed a method to amplify Asyn fibrils derived from human post-mortem LBD brain tissue and determined that the structure of amplified Asyn fibrils is highly similar to the structure of fibrils directly isolated from LBD brain tissue. We examined whether injection of these fibrils into humanized Asyn mice recapitulates pathologic Asyn fibril accumulation with human LBD Asyn fibril structure. We utilized mice containing a null allele in the mouse Snca gene and a human SNCA transgene. Intrastriatal injection of amplified Asyn fibrils derived from 3 different LBD autopsy cases resulted in cytoplasmic and neuritic phospho-Asyn accumulation in the striatum, cortex, and amygdala bilaterally at 3mpi. Fibril injections produced a reduction in the number of dopaminergic neurons in the substantia nigra, with LB-like inclusions in surviving neurons, and produced impaired sensorimotor function as measured on the accelerating rotarod test. Fibril accumulation increased 3.6-fold between 1 and 3 months post-injection (mpi) and was relatively stable between 3 and 5 mpi. We amplified fibrils from mouse brain tissue 5 mpi and collected single-particle cryo-EM data. High resolution 3D structural information could not be obtained because of the lack of helical twist, but comparison of the cryo-EM 2D class averages with those derived from amplified fibrils prepared from human LBD tissue revealed multiple matching classes, indicating that the Lewy fold is maintained in the fibrils that accumulate in mouse brain tissue. Our findings demonstrate an approach to model the accumulation of Asyn fibrils with LBD structure in mice, providing a platform for investigating disease mechanisms, imaging biomarkers, and therapeutics targeting Asyn in PD/LBD.