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Maria-Tzousi Papavergi, MS


Job Title

PhD student

Academic Rank

Grad student




Maria-Tzousi Papavergi, Brijendra Singh, Andre F. Batista, Praveen Bathini, Emma Spooner, Shaomin Li, and Cynthia A. Lemere

Principal Investigator

Cynthia Ann Lemere



A MaGical cASe: a story of the cell-specific effects of C3-mediated neurodegeneration

Scientific Abstract

Synapse loss is a critical feature of Alzheimer’s disease (AD). C3 is the molecule at which multiple complement signaling pathways converge and has emerged as a key factor in synapse elimination during aging and AD. We aimed to define the underlying cell-specific mechanisms of either microglia or astrocytes that lead to C3-dependent synaptic toxicity and neurodegeneration. To this end, we generated cell-specific C3 tamoxifen (TAM)-inducible conditional knock-out (KO) mice to allow for specific KO of C3 in microglia (C3mg-iKO) and astrocytes (C3as-iKO). Young adult mice were injected intraperitoneally with either corn oil as control or TAM. Aged TAM-treated C3mg-iKO mice performed significantly better in behavioral tests of spatial memory, showed a modest lowering of C3 and C1q protein levels in the hippocampus and a 30% lowering of C3 mRNA expression levels compared to controls. Aged TAM-treated C3as-iKO mice demonstrated a modest increase in post-synaptic density in the hippocampus and a 50% lowering of C3 and clusterin mRNA expression levels compared to controls. C3 lowering in astrocytes significantly protected hippocampal synapses from Aβ-dimer-mediated LTP impairment in TAM-treated C3as-iKO mice. These results highlight the interactions of C3 and glial cells as a crucial component in investigating synapse loss during aging and AD.

Lay Abstract

Alzheimer’s disease (AD) is the most prevalent type of dementia. Synapses are the points in the nervous system where neurons communicate, and synapse loss can lead to AD. The complement cascade is a powerful part of our innate immune system. Complement C3 is a central component of this cascade. Besides its role in helping fight pathogens, C3 plays a crucial part in brain development, aging and AD by eliminating weak synapses. Microglia and astrocytes are glial cells in our brains with an essential role in the immune response. Astrocytes are the primary source of C3 in the brain, but C3 expression is enhanced in microglia once activated. Therefore, we engineered mouse models that allow us to reduce, in a cell-specific manner, C3 expression in microglia and astrocytes, to investigate the underlying mechanisms that lead to C3-dependent neurodegeneration. C3 lowering in microglia significantly improved spatial memory in mice and led to a modest decrease in C3 levels in the brain. C3 lowering in astrocytes significantly protected synapses in the brain and resulted in decreased C3 levels. Our study highlights the necessity of exploring the interactions between C3 and glial cells during aging and AD.

Clinical Implications

Understanding the cell-specific mechanisms that lead to C3-mediated neurodegeneration will help us unravel the role of the complement cascade in synaptic loss and identify therapeutic targets that may prevent or slow disease progression in AD and other neurodegenerative disorders.