Modulation of C5a–C5aR1 signaling alters the dynamics of AD progression

• Main Authors: Carvalho, Klebea, Schartz, Nicole D, Balderrama-Gutierrez, Gabriela, Liang, Heidi Y, Chu, Shu-Hui, Selvan, Purnika, Gomez-Arboledas, Angela, Petrisko, Tiffany J, Fonseca, Maria I, Mortazavi, Ali, Tenner, Andrea J
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: eScholarship, University of California 2022
• Subjects: Biomedical and Clinical Sciences; Neurosciences; Immunology; Neurodegenerative; Aging; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Brain Disorders; Dementia; Genetics; Acquired Cognitive Impairment; Aetiology; 2.1 Biological and endogenous factors; Neurological; Alzheimer Disease; Animals; Biological Phenomena; Mice; Microglia; Plaque; Amyloid; Receptor; Anaphylatoxin C5a; Signal Transduction; Complement; Inflammation; C5aR1; C5a; Disease-associated microglia; Mouse model; Therapeutic target; Alzheimer’s disease; Clinical Sciences; Neurology & Neurosurgery; Arctic
• Online Access: https://escholarship.org/uc/item/4qn6978q

BackgroundThe complement system is part of the innate immune system that clears pathogens and cellular debris. In the healthy brain, complement influences neurodevelopment and neurogenesis, synaptic pruning, clearance of neuronal blebs, recruitment of phagocytes, and protects from pathogens. However, excessive downstream complement activation that leads to generation of C5a, and C5a engagement with its receptor C5aR1, instigates a feed-forward loop of inflammation, injury, and neuronal death, making C5aR1 a potential therapeutic target for neuroinflammatory disorders. C5aR1 ablation in the Arctic (Arc) model of Alzheimer's disease protects against cognitive decline and neuronal injury without altering amyloid plaque accumulation.MethodsTo elucidate the effects of C5a-C5aR1 signaling on AD pathology, we crossed Arc mice with a C5a-overexpressing mouse (ArcC5a+) and tested hippocampal memory. RNA-seq was performed on hippocampus and cortex from Arc, ArcC5aR1KO, and ArcC5a+ mice at 2.7-10months and age-matched controls to assess mechanisms involved in each system. Immunohistochemistry was used to probe for protein markers of microglia and astrocytes activation states.ResultsArcC5a+ mice had accelerated cognitive decline compared to Arc. Deletion of C5ar1 delayed or prevented the expression of some, but not all, AD-associated genes in the hippocampus and a subset of pan-reactive and A1 reactive astrocyte genes, indicating a separation between genes induced by amyloid plaques alone and those influenced by C5a-C5aR1 signaling. Biological processes associated with AD and AD mouse models, including inflammatory signaling, microglial cell activation, and astrocyte migration, were delayed in the ArcC5aR1KO hippocampus. Interestingly, C5a overexpression also delayed the increase of some AD-, complement-, and astrocyte-associated genes, suggesting the possible involvement of neuroprotective C5aR2. However, these pathways were enhanced in older ArcC5a+ mice compared to Arc. Immunohistochemistry confirmed that C5a-C5aR1 ...