Age‐Related Complement <scp>C3</scp> Drives Memory Impairments and Associated Neuropathologies in a Mouse Model

Aging is the greatest risk factor for learning and memory disorders; dementia prevalence significantly increases with age due to numerous molecular changes in the body. Although research has consistently shown that aging leads to learning and memory impairments, the molecular mechanisms linking aging to these cognitive deficits remain incompletely understood. Previous studies have revealed that complement C3 levels increase with age in humans, monkeys, and mice; elevated C3 expression is also observed in the brains of dementia patients. These data suggest that C3 plays critical roles in initiating learning and memory impairments. To investigate whether C3 contributes to these deficits during aging, we developed a transgenic mouse model with elevated C3 expression to simulate age-related increases. Mice with increased C3 expression showed impaired learning and memory, along with synaptic loss, neuronal loss, and astrocytosis. Quantitative polymerase chain reaction microarray and cellular assays revealed that C3 elevation may impair cognitive functions by affecting insulin signaling pathways. Notably, antibody therapy targeting complement C3 in SAMP8 mice, which naturally exhibit increased brain C3 levels, alleviated their learning and memory deficits. These findings suggest that age-related complement C3 elevation drives memory impairments and associated neuropathologies; targeting complement C3 may alleviate these deficits.