Advisor: Kerry O’Banion, Ph.D. - Ph,D, Thesis Proposal
Alzheimer’s disease (AD) is the most common form of dementia and its prevalence is expected to rise. The most striking molecular pathology in AD is the extracellular protein aggregates, termed amyloid plaques. It is established that peripheral immunomodulatory interventions can alter this histopathological hallmark and are associated with improved outcomes. Our lab has previously observed that the relapsing remitting Multiple Sclerosis (MS) drug Glatiramer Acetate (GA, Copaxone®) can improve amyloid and tau pathology, and ameliorate cognitive impairments in the 3xTg AD mouse model. Although our group and others have shown that GA treatment decreases amyloid pathology across a variety of models, the exact mechanism of this elusive drug, even in its principle applications, remains unclear. Similar to the findings from literature concerning animal models of MS, we hypothesize that GA modulates both CD4+ T cell and monocyte function towards a phenotype more conducive to tissue repair and homeostasis, and both these cell types have potential to mediate protection from amyloid pathology.
In Aim 1, we will investigate the necessity and sufficiency of CD4+ T cells in GA’s mechanism of action through antibody-mediated depletion studies under GA treatment and adoptive transfers of CD4+ T cells from GA vaccinated donors into 5xFAD hosts which develop amyloid pathology much faster than other common AD models. In addition, we will test whether a Th2 transcriptional profile and migration into the brain parenchyma, the two components of “bystander suppression” hypothesis, are required for GA’s mechanism in AD. In Aim 2, we will investigate whether monocytes are sufficient and necessary in GA’s mechanism of action by adoptive transfer of monocytes isolated from GA treated mice and liposome mediated depletion studies. Furthermore, we will confirm that GA modulates the expression of several key transcripts in monocyte phenotype and also attempt to understand the crosstalk between monocytes and CD4+ T cells in development of a response to GA by adoptively transferring monocytes from GA treated Rag2-/- donors. Altogether, this project will identify key, easily accessible peripheral immune players in GA’s mechanism. Greater understanding in this domain will help repurpose a drug with an excellent safety profile to a new context and give insights into the impact of peripheral immune cell types in AD.
Dec 11, 2019 @ 10:45 a.m.
Medical Center | 3-7619 Upper Auditorium