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He/Him/His
Job Title
Postdoctoral research fellow
Academic Rank
Fellow or Postdoc
Department
Neurology
Authors
Brijendra Singh1, Andre F. Batista1, Maren K. Schroeder2, Khyrul Khan2, Emma Spooner2,; Takaomi Saido3; Michael C. Carroll4, Cynthia A. Lemere1
Principal Investigator
Cynthia A. Lemere
Categories
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Complement C3, a central component of the complement cascade, is elevated with aging and participates in synaptic elimination in neurodegenerative diseases like Alzheimer’s diseases (AD). Here, we generated an amyloid mouse model in which we could induce global C3 knockdown at any age (APPNL-G-F/NL-G-FxC3fl/fl Rosa26CreERT2 = APP;C3iKO mice) and injected them with either corn-oil (CO) as a control or Tamoxifen (TAM) to lower C3 for 5 consecutive days at ~3.6 months of age. TAM-injected mice showed an 85% reduction of serum C3 protein confirmed by C3-ELISA. TAM-injected mice had better cognition at 15 months when compared to CO-injected mice. At 15-16 months of age, cerebral C1q and C3 protein levels were reduced in TAM-injected mice. There were no significant changes in Aβ plaques or glial cells. However, Aβ-associated CD68-positive microglia were significantly reduced in TAM-injected mice indicating less macrophagic activity near plaques. Synaptic markers (SYN, PSD95, Bassoon, Homer1) were elevated in TAM-injected mice, and bulk RNAseq revealed 1071 differentially expressed genes (DEGS), with key DEGs linked to synaptic function indicating that C3 lowering early in plaque deposition protected against age-associated synapse elimination and cognitive decline. Our results suggest that targeting complement-related pathways may be neuroprotective.
The accumulation of toxic proteins in the brain known as amyloid plaques leads to memory loss and cognitive impairment in Alzheimer’s disease. Past studies have shown that even in animals with these plaques, eliminating an immune-related protein known as complement C3 helped preserve memory and brain connections. In this work, we investigated whether lowering C3 might have a comparable effect in a mouse model with Alzheimer’s disease amyloid plaques. Through genetic engineering, we were able to produce mice whose C3 levels could be reduced with the drug called tamoxifen. After injecting with tamoxifen, these mice showed significant improvements in memory and cognitive tests compared to control mice. While the amyloid plaques remained unchanged, the brains of tamoxifen-treated mice had reduced inflammation and healthier brain connections. These findings suggest that reducing C3 in adult mice can protect the brain from Alzheimer’s-related damage. We are continuing our work to better understand which other proteins are affected by C3 lowering, as this might offer insights into potential future treatments for the disease.
