Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is the main cause of dementia in the elderly population. AD is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles that results in neurodegeneration and loss of memory function. However, diagnosis of AD and characterization of biological mechanisms that lead to pathology and modulate risk for disease has proven to be extremely difficult. Cerebrospinal fluid (CSF) contains critical biomarkers for AD such as levels of amyloid beta (Aβ) phosphorylated-tau (p-tau), total-tau (t-tau), and neurofilament light chain (NfL). The CSF levels of these biomarkers are useful in determining AD status in a patient, but data collection can be time consuming, technically difficult, and expensive. While still subject to the limitations of obtaining CSF, cell free single stranded DNA (cfssDNA) is much cheaper and more reliably measured than these biomarkers. We investigated cfssDNA as a biomarker for AD status. We observed an association between low levels of concentration isolated from CSF as a potential biomarker for diagnosis of AD. Inflammation is a vital process in the immune system. Acute inflammation plays an essential role in the normal response to tissue injury. This inflammatory response initiates a cascade of cellular activation signals in innate immune cells resulting in increased production of proinflammatory cytokines and chemokines. These chemokines are essential to the recruitment and activation of other cells in the innate and adaptive immune system. Deviations from the normal production of these chemokines can result in disease status. Recently published work has identified genetic variants that show strong associations with AD-related chemokine levels in CSF and plasma. We attempted to characterize the biological mechanisms that underlie the reported associations between the ACKR2-V41A variant and CCL2 levels and the CCRL2-V180M variant and CCL4 levels. Our data demonstrate that the ACKR2-V41A receptor has a lower CCL2 binding affinity, scavenging efficiency, and receptor upregulation compared to ACKR2-WT. For CCRL2-V180M our data demonstrate higher binding affinity with chemerin and CCL19 than CCRL2-WT. Our data also show that while CCRL2-V180M and CCRL2-WT do not directly bind with CCL4, interactions between CCRL2-V180M and CCL19 alter the secretion of CCL4 from leukocytes. These findings provide evidence for a novel biomarker for AD diagnosis, mechanistic insights into the functional impact of common genetic variants on chemokine levels, and highlight a potential role of atypical chemokines in altering the risk for AD.

Degree

PhD

College and Department

Life Sciences; Biology

Rights

https://lib.byu.edu/about/copyright/