Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 10, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-022-01416-6
Keywords
C5aR1; Alzheimer's disease; Microglia; Complement; Neuroinflammation; DAM
Categories
Funding
- NIA [R21 AG061746, R01 AG060148]
- Larry L. Hillblom postdoctoral fellowship [2021-A-020-FEL]
- Alzheimer's Association Research Fellowship [AARFD-20-677771]
- Edythe M. Laudati Memorial Fund
- Cancer Center Support Grant at the University of California, Irvine [CA-62203]
- Center for Complex Biological Systems Support Grant at the University of California, Irvine [GM-076516]
- [T32 AG00096]
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Multiple studies have shown the involvement of the complement cascade in the progression of Alzheimer's disease, but the specific role of C5a-C5aR1 signaling in this neurodegenerative disease is still unclear. However, using the C5aR1 antagonist PMX205 in a mouse model of Alzheimer's disease has shown promising results in reducing neurodegeneration, amyloid load, and synaptic loss, suggesting its potential as a therapeutic target.
Multiple studies have recognized the involvement of the complement cascade during Alzheimer's 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 Alzheimer's disease exerted a protective effect by preventing cognitive deficits. Here, using PMX205, a potent, specific C5aR1 antagonist, in the Tg2576 mouse model of Alzheimer's 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 Alzheimer's 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.
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