Tau, amyloid-β and α-synuclein co-pathologies synergistically enhance neuroinflammation and hippocampal neuron loss

Alzheimer's (AD) and Parkinson's disease (PD) pathology often co-occur. Amyloid-β and phosphorylated tau are found in 30-50% of idiopathic PD cases, while α-synuclein inclusions are present in over 50% of AD cases. These co-pathologies are linked to increased mortality and earlier onset of cognitive decline. Immune activation is a hallmark of these neurodegenerative diseases, but current model systems primarily examine each pathology in isolation. As such, how these co-pathologies drive inflammation and neuronal loss remains poorly understood. To address this gap, we developed a mouse model combining tau, amyloid-β, and α-synuclein as co-pathologies. We found that co-pathologies synergistically trigger a distinct and amplified neuroimmune response, marked by robust expansion of CD4⁺ and CD8⁺ tissue-resident memory T cells and CD68⁺ microglia, a population of activated, phagocytosing microglia, compared to single pathologies. These changes were abundant in the hippocampus and cortex, regions that showed elevated protein pathology load at 3- and 6-months post-induction and enhanced neuronal loss at 6-months post induction. Our findings demonstrate that co-pathologies promote accumulation of proteinopathy and synergistically enhance immune activation in the hippocampus and cortex and hippocampal neuronal loss. With this model as a novel tool to assess mixed-pathology mechanisms, our results support the need for combinatorial therapeutic strategies, that target both co-pathologies and inflammation, and identifies neuroinflammation as a prominent feature associated with co-pathology enhanced neurodegeneration.