Abstract

Besides the pathological hallmarks of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs), increasing evidence suggests that neuroinflammation plays a significant role in AD pathogenesis. The complement pathway is a key regulator of innate immunity. Recent findings from our laboratory showed that the central complement component C3 is upregulated in astrocytes of AD patients and mouse models. Moreover, elevated astroglial C3 can modulate Aβ dynamics and pathology and reduce dendritic morphology and synaptic function through microglial and neuronal C3a receptor (C3aR), respectively. Giving the importance of the C3-C3aR axis in the CNS, we are interested in understanding whether the complement pathway also impacts the NFT pathology. We analyzed the expression patterns of complement pathway genes in AD, MCI and non-cognitive impaired brain samples obtained from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) cohorts and in the PS19 mouse model of tauopathy before or after the onset of NFT pathology. Next, we studied the functional effects of the C3-C3aR pathway on reactive gliosis and NFT pathology by genetically deleting C3aR or overexpressing neuronal C3aR in PS19 animals. Finally, we utilized RNA sequencing and reverse-phase proteomics (RPPA) to identify C3aR downstream signaling pathways that promote such effects. Analysis of RNA sequencing datasets from human brains revealed a strong upregulation of complement pathway genes that is highly correlated with Braak staging and cognitive decline. Prominent complement upregulation was also observed in PS19 mice in response to NFT pathology. AAV-driven neuronal overexpression of C3aR exacerbates tau/NFT pathology in PS19 animals. Conversely, knocking out C3aR in PS19 mice results in significant reduction of inflammation, phospho-tau levels and associated pathology and improved behavioral deficits of PS19 animals. Mechanistically, we identify the Jak-Stat3 pathway as a potent regulator of reactive gliosis and tau pathology in PS19 mice downstream of C3aR.

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