Fellow or Postdoc
Brijendra Singh, Andre F. Batista, Maren K. Schroeder, Khyrul Khan, Emma Spooner, Takashi Saito; Hiroki Sasaguri; Takaomi Saido; Michael C. Carroll, Cynthia A. Lemere
Dr. Cynthia A. Lemere
Complement C3 is an innate immune component of complement cascade, elevated with aging, participates in synaptic elimination in neurodegenerative diseases like Alzheimer’s diseases (AD). We hypothesized that C3 lowering during the early stages of AD would be neuroprotective later in life. We generated an amyloid mouse model in which we could induce global C3 knockdown at any age (APP;C3iKO mice) and injected them with either corn-oil (CO) or Tamoxifen (TAM) for 5 consecutive days at ~3.6 months of age. TAM-injected mice showed an 85% reductionof 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. TAM-injected mice also showed an increase in postsynaptic marker (PSD-95), indicating less synaptic degeneration indicating thatC3 lowering after the onset of plaque deposition protected against age-associated synapse elimination and cognitive decline.
Complement protein (C3) is one of the important components of our body’s defense system called the complement cascade which helps our immune system attack harmful invaders like bacteria and viruses. It can poke a hole in these invaders and make it easier for immune cells to destroy them. Also, C3 participates in synaptic connectivity, which is wiring in the brain that allows nerve cells to communicate with each other. However, In Alzheimer disease (AD), role of the C3 protein is not well known. Normally, C3 protein acts as a security system to protect from threats. With aging or in AD patients, C3 protein becomes overactive and instructs immune cells in the brain to remove not only the harmful agents like amyloid, a hallmark of AD, but also the healthy brain cells and synaptic connections that ultimately leads to decrease in a person’s ability to think, learn, everyday tasks. In our study, the C3 protein level was reduced ~85% in our genetically engineered mice which resulted in better memory with more synaptic strength and less inflammation near the plaques when compared with mice without C3 lowering.