Defense Date

4-20-2022

Document Type

Thesis

Degree Type

Master of Science

Degree Name

Biological Sciences

First Advisor

Alexandru Movila, Ph.D.

Second Advisor

Lubov Nathanson, Ph.D.

Third Advisor

Andrew Ozga, Ph.D.

Fourth Advisor

Veronica Fortino, Ph.D.

Keywords

Late-Onset Alzheimer’s Disease, Neuroinflammation, Amyloid-beta, Bone Osteolysis, Interleukin-34, Macrophage colony-stimulating factor, RANKL-mediated osteoclastogenesis, Osteoclast precursor, Cognitive behavior, Triple-transgenic mice

Abstract

Alzheimer’s disease (AD) is a growing health concern and is the most common type of dementia worldwide. Emerging evidence indicates that aggregated amyloid-beta (Aβ) peptides, one of the hallmark features of AD neuropathology, can increase RANKL-mediated osteoclast activity leading to the prevalence and severity of inflammatory osteolysis, e.g., osteoporosis and periodontal bone loss. Conversely, osteolytic lesions are associated with increased risk of dementia diagnosis indicating that there is a direct link between dementia and inflammatory osteolysis. It was demonstrated that the neuronal cells primarily produce interleukin-34 (IL-34) and microglia, macrophages, and osteoclast precursors express colony-stimulating factor 1 receptor (CSF-1R), a cognate receptor for IL-34. Similar to IL-34, macrophage colony stimulating factor (M-CSF) also promotes bone marrow (BM)-derived monocyte survival and differentiation into macrophages. While M-CSF has been extensively studied, the biology and functions of IL-34 are only now beginning to be uncovered. We recently reported the differences in the inflammatory signal transduction and polarization of IL-34 and M-CSF-macrophages in response to COVID-19 Spike protein. In addition, published observations demonstrated that IL-34 is relevant to innate immune responses in AD. Based on these lines of evidence, we hypothesized that IL-34 plays an essential role in the promotion of inflammatory bone osteolysis and neuroinflammation associated with AD. Using 3x-triple AD transgenic mice and their wild type, we found that the number of multinucleated osteoclasts were significantly increased from IL-34-polarized osteoclast precursors (OCPs) compared to M-CSF-OCPs in the presence of various Aβ peptides in vitro as well as in a mouse model of calvarial osteolysis. In addition, local calvaria injection of recombinant IL-34 protein increased immobility, fecal boli, and freezing behaviors in female 3x-Tg-AD mice in comparison to male. We also identified that IL-34 significantly elevated expression patterns of various markers associated with AD pathology, including Aβ, hyperphosphorylation of tau, Zonula occludin-1 (ZO- 1), receptor-associated protein (RAP), receptor of advanced glycosylation end- products (RAGE), Occludin, and Neuronal nuclear protein (NeuN) in female 3x-Tg-AD mice. No or little effect of IL- 34 was observed in male 3x-Tg-AD mice indicating that IL-34 promotes sex- dependent AD pathology and bone osteolysis. Furthermore, the amount of elevated production of senescence-associated secretory phenotype (SASP) markers of pro-inflammatory cytokines, e.g., TNF-α, IL-6 and IL-1β, IL-34-macrophages and -microglia cells were significantly elevated compared to those that were proliferated by M-CSF. Overall, our results highlight the challenges of targeting the IL-34 in the systemic and central compartments, important for framing any therapeutic effort to tackle bone loss, and neuroinflammation, and neurodegeneration during AD.

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