The Tenner laboratory is contributing to the emerging understanding of the role of the complement system in directing an appropriate immune response, with a specific focus on neurodegenerative conditions like Alzheimer’s disease (AD). Our lab is highly collaborative and supportive of Team science.

We are completing preclinical studies necessary to establish rationale for a clinical trial testing an antagonist of the C5a receptor 1 as a treatment for AD and/or other acquired cognitive disorders caused by aging, cancer, neurodegeneration or other injury. In AD, the complement pathway (which is normally protective during infection) is activated by amyloid fibrils (and later by hyperphosphorylated tau) and can cause detrimental inflammation and neurotoxicity in an accelerating cycle of microglial and astrocyte activation. Administering a specific inhibitor of this inflammatory event improved cognitive performance and suppressed neuronal pathology in AD mouse models suggesting that this strategy may be a beneficial treatment to slow the progression of AD. With our UCI collaborators we currently are defining the molecular pathways involved in these processes using bulk, single-cell and single nucleus RNA-Seq, immunohistochemistry, and behavior, and aligning our results to characteristics of human AD.

Early components of the complement cascade play a role in a normal process of synaptic pruning. The mechanisms regulating synaptic pruning is now being actively explored by many laboratories during neuronal development, normal synaptic plasticity, and as a contributor to cognitive loss seen in neurodegenerative or neurological disorders. While beneficial during development, whether induction of excessive pruning may contribute to detrimental effects in certain disorders in the adult, such as AD, is currently under investigation. Our lab uses superresolution and high resolution confocal microscopy to explore this activity in mouse models and its effect on cognition during aging and neurodegenerative disorders.

We have also identified a neuroprotective pathways mediated by the complement component C1q (in the absence of the other complement components). C1q increases the response of the body’s scavenger cells, including microglia, to ingest dying cells and cellular debris and modifies the scavenger cell’s gene expression to promote an anti-inflammatory response, all of which are beneficial in the brain (as well as protective against autoimmunity). Furthermore, C1q is neuroprotective toward the toxic effects of amyloid fibrils. Thus, another current goal in the Tenner laboratory is to investigate these C1q-mediated neuroprotective pathways using both in vitro human iPSC derived neurons and in vivo with an inducible conditional knock out of C1q in mouse models of AD. The goal is to develop a therapeutic strategy to enhance neuronal resilience, which may then be coupled with the above mentioned anti inflammatory C5aR1 antagonist as a combination therapy for neurodegenerative diseases.