Microglial Responses to Cell-free DNA in Alzheimer's Disease

Project Summary/Abstract This Mentored Patient-Oriented Research Career Development Award application is for Dr. Lolita Nidadavolu, Assistant Professor of Medicine in the Division of Geriatric Medicine and Gerontology at the Johns Hopkins University School of Medicine. Dr. Nidadavolu’s long term goal is to establish an independent research career

in Alzheimer’s Disease (AD) focused on disease-associated changes in innate immune signaling and cell-free DNA (cf-DNA). To achieve this goal, the candidate has assembled an interdisciplinary team that includes experts in AD, clinical trials, gerontology, chronic inflammation, microglia biology, and biostatistics. The proposed

research for this Career Development Award addresses the critical need to further understand chronic inflammation in AD, which may lead to development of novel treatment options targeting inflammation. Microglia, the resident immune cells of the central nervous system, are major contributors to chronic inflammation in AD.

However, a knowledge gap remains in understanding factors that contribute to microglial activation and dysfunction in AD. One proposed contributor to AD-associated microglial activation is cell-free DNA, which is released following cell death processes and can be measured in serum. Prior studies demonstrate that

individuals with elevated levels of cf-DNA in serum have lower cognitive test scores and a higher risk of developing AD. Additional preliminary evidence shows that patient-derived cf-DNA is sufficient to upregulate inflammatory cytokines in microglia in vitro. The hypothesis of this proposal is that cf-DNA are associated with

microglia activation and can activate pro-inflammatory pathways known to be upregulated in AD. This proposal will use serum and autopsy samples from Rush Alzheimer’s Disease Center (RADC) Religious Orders Study and Memory and Aging Project (ROS-MAP) participants as well as Johns Hopkins Precision Medicine Center of

Excellence in Alzheimer’s Disease (PMCoE-AD) and the Johns Hopkins Older American’s Independence Center (OAIC) to examine associations between cf-DNA and disease-associated microglial activation. First, associations will be examined between serum cf-DNA levels and microglia activation (Aim 1). Next, functional

changes in microglia phagocytosis and pro-inflammatory pathway activation will be studied in human inducible pluripotent stem cell-derived microglia exposed to purified cf-DNA from individuals with AD and normal cognition controls (Aim 2 and 3). The successful completion of the proposed research will lead to a better understanding

of associations between cf-DNA and microglia activation in AD. Additionally, the collaborations and training in this Career Development Award will provide the coursework, research experience, clinical trial skills, and mentorship to solidify the applicant’s expertise as an independent clinician scientist and leader in microglia

function and dysregulation in AD.