C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimers disease

Gomez-Arboledas, A.; Carvalho, K.; Balderrama-Gutierrez, G.; Chu, S.-H.; Liang, H. Y.; Schartz, N. D.; Selvan, P.; Petrisko, T. J.; Pan, M. A.; Mortazavi, A.; Tenner, A. J.

doi:10.1101/2022.05.18.492363

bioRxiv · 10.1101/2022.05.18.492363

C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimers disease

Gomez-Arboledas, A.·Carvalho, K.·Balderrama-Gutierrez, G.·Chu, S.-H.·Liang, H. Y.·Schartz, N. D.·Selvan, P.·Petrisko, T. J.·Pan, M. A.·Mortazavi, A.·Tenner, A. J.

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Abstract

Multiple studies have recognized the involvement of the complement cascade during Alzheimers disease pathogenesis; however, the specific role of C5a-C5aR1 signaling in the progression of this neurodegenerative disease is still not clear. Furthermore, its potential as a therapeutic target to treat AD still remains to be elucidated. Canonically, generation of the anaphylatoxin C5a as the result of complement activation and interaction with its receptor C5aR1 triggers a potent inflammatory response. Previously, genetic ablation of C5aR1 in a mouse model of Alzheimers disease exerted a protective effect by preventing cognitive deficits. Here, using PMX205, a potent, specific C5aR1 antagonist, in the Tg2576 mouse model of Alzheimers disease we show a striking reduction in dystrophic neurites in parallel with the reduced amyloid load, rescue of the excessive pre-synaptic loss associated with AD cognitive impairment and the polarization of microglial gene expression towards a DAM-like phenotype that are consistent with the neuroprotective effects seen. These data support the beneficial effect of a pharmacological inhibition of C5aR1 as a promising therapeutic approach to treat Alzheimers disease. Supportive of the safety of this treatment is the recent FDA-approval of another other C5a receptor 1 antagonist, Avacopan, as a treatment for autoimmune inflammatory diseases. One Sentence SummaryC5aR1 antagonist shifts microglial gene expression toward neuroprotection.

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Gomez-Arboledas, A., Carvalho, K., Balderrama-Gutierrez, G., Chu, S.-H., Liang, H. Y., Schartz, N. D., Selvan, P., Petrisko, T. J., Pan, M. A., Mortazavi, A., Tenner, A. J.. 2022-05-19. C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimers disease. https://doi.org/10.1101/2022.05.18.492363

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