| First Author | Puntambekar SS | Year | 2022 |
| Journal | Mol Neurodegener | Volume | 17 |
| Issue | 1 | Pages | 47 |
| PubMed ID | 35764973 | Mgi Jnum | J:351092 |
| Mgi Id | MGI:7311014 | Doi | 10.1186/s13024-022-00545-9 |
| Citation | Puntambekar SS, et al. (2022) CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimer's disease. Mol Neurodegener 17(1):47 |
| abstractText | BACKGROUND: Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Abeta driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood. METHODOLOGY: Accumulation of soluble and insoluble Abeta species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1(+/+) and 5xFAD;Cx3cr1(-/-) mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Abeta uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04(+) fibrillar Abeta. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory. RESULTS: Disease progression in 5xFAD;Cx3cr1(-/-) mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Abeta phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1(-/-) mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Abeta, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFbeta-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1(-/-) mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1(-/-) mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1beta, Pten and Cybb along with reduced Tnf, Il-6 and Tgfbeta1 mRNA. CONCLUSIONS: Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Abeta, thereby triggering increased accumulation of neurotoxic Abeta species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFbeta-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Abeta-driven microglial dysfunction in Cx3cr1(-/-) mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory. |
