Alzheimer?s disease (AD) is an age-related neurodegenerative disorder defined by the deposition of ?-amyloid (A?) plaques and accumulation of neurofibrillary tangles (NFTs), of which the principal components are A? peptides derived from the amyloid precursor protein (APP) and hyper-phosphorylated Tau, respectively. The relationship between the extracellular A? and intracellular NFT pathologies and how aging contributes to the disease pathogenesis are critical questions but remain poorly understood. Besides the pathological hallmarks, AD is associated with profound neuroinflammation marked by reactive astrogliosis and microgliosis. The complement pathway is a well-recognized innate immunity modulator. We uncovered an astroglial C3 and neuronal and microglial C3a receptor (C3aR) mediated neuron-immune signaling network that is prominently elevated in human AD and in AD mouse models where inactivation of C3aR ameliorates AD pathology and cognitive impairment. Since C3aR is widely expressed in the central nervous system, the C3aR blockade could exert its beneficial effects by acting on these cell types individually or by influencing the neuron-immune network. Indeed, crosstalk between microglia, astrocytes, and neurons has long confounded elucidation of their individual roles in neuroinflammatory damage. To tackle this problem, we have created a C3ar1 conditional allele that allows us to inactivate the C3aR in different cell types in the CNS and delineate their cell- type-specific roles. We have also developed a powerful technology that enables us to isolate high-quality RNA and to perform RNA sequencing analysis from aged dissociated and fluorescence-activated cell sorting (FACS) sorted individual neurons, astrocytes, and microglia. This affords unbiased analysis of central immune and inflammatory pathways with unprecedented cellular specificity. Building on these exciting biological and technical developments, we propose to a) decipher the role and cell-type-specific contribution of C3-C3aR pathway in AD pathogenesis using APP knock-in mouse models; b) interrogate cell-type-specific changes as a function of A? pathology and C3aR ablation and identify common signatures in human AD; c) determine the cellular mechanisms underlying complement mediated Tau/NFT pathology. These will provide unprecedented insights into the cell-type-specific targets in AD pathogenesis and we are equipped with innovative technology and sophisticated mouse models to address these questions.
The proposed research is relevant to public health because it will provide fundamental knowledge about the cell-type-specific changes in the brain during aging and the consequential impacts on the progression of Alzheimer?s disease. We will investigate the neuron-immune interaction networks and functional contribution of the complement pathway in aging and Alzheimer?s disease using cutting-edge technology. These studies are expected to identify novel pathogenic mechanisms and potential therapeutic targets for Alzheimer?s disease.
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