Amyloid-beta, alpha-synuclein and tau aggregated co-pathologies enhance neuropathology and neuroinflammation

Lewy pathology due to alpha-synuclein (α-syn) inclusions is one of the major hallmarks of Parkinson’s Disease (PD). β-Amyloid (Aβ) and phosphorylated-tau, pathologies usually found in Alzheimer’s Disease (AD), have also been implicated in PD, with over 50% of patients exhibited the co-expression of these proteins (co-pathologies). In both AD and PD postmortem tissue, neuroinflammation – the activation of microglia and resident macrophages and the infiltration of immune cells from the periphery, including T cells and monocytes–are drivers of neurodegeneration. However, how the co-expression of these pathologies contribute to the inflammatory response and overall neurodegenerative disease phenotype remains unknown. To understand how the co-expression of pathologies drives neuropathology, we developed a novel co-pathology model by stereotaxically injecting α-syn pre-formed fibrils (PFFs) into the striatum, and AAV-double ^mut tau virus into the entorhinal cortex, of 3-month-old J20 transgenic mice with Aβ pathology. We analyzed immune cell populations in the brain and periphery at 3 months post-induction (3MPI). At 6MPI, neuronal loss in the hippocampus and substantia nigra pars compacta were assessed along with pathological protein deposition. At 3MPI, the co-pathology mouse model begins to exhibit enhanced pathology load in the cortex and hippocampus. There was a robust neuroinflammatory response in interconnected brain regions, including increased microglial cell number, changes in microglial activation markers, and infiltration of T cells. This was synergistic in the co-pathology model, compared to the individual models, supporting the hypothesis that these collectively may drive the progression of disease.