The basic understanding of the immune system has undergone a substantial paradigm shift in the past decade as an awareness of the power and influence of the innate immune system has emerged. Essentially, it is now being recognized that the nature of the first response to invasion has significant influence in determining the nature of the subsequent adaptive immune response. That is, it is this first response that assesses the level of danger of a particular intrusion or injury and initiates a program of protection.
A major research area is the investigation of the role of complement activation and subsequent inflammation in Alzheimer’s Disease. The neuropathological structures that are the hallmark of Alzheimer’s disease (AD) include senile plaques composed of a proposed pathogenic peptide fragment, beta-amyloid (A-Beta), neurofibrillary tangles and loss of neurons. Using mouse models of AD, we have evidence consistent with the hypothesis that complement activation and subsequent inflammatory events contribute to the pathogenesis of dementia in AD, and are currently validating candidate therapeutic targets to prevent or slow the progression of pathogenic events that lead to Alzheimer’s Disease in mouse models. In addition, while C1q and the early components of the complement system are involved in synapse pruning, we postulate that C1q may be a response to injury that could play a protective role in the early stages of disease by enhancing the clearance of cellular debris, altering the effects of the amyloid peptide on microglia, and/or providing direct neuroprotective effects. We are currently usinghuman iPSC neurons and inducible C1q ablation in mouse models of AD to test these hypotheses.
We are also completing the 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. 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. We currently are defining the molecular pathways involved in these processes using bulk and single-cell RNA-Seq, immunohistochemistry, and behavior, and aligning our results to characteristics of human AD.
Additional long standing interests in the laboratory include the role of specific elements of the innate immune system in host defense and in maintaining a balance of peripheral protective responses in the host. Thus, we are investigating the down stream events such as cytokine expression resulting from the interaction of defense collagens in the context of various particles targeted for ingestion.