Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Paula C. Bickford, Ph.D.

Co-Major Professor

Daniel C. Lee, Ph.D.

Committee Member

Kevin Nash, Ph.D.

Committee Member

Lynn Wecker, Ph.D.

Committee Member

Craig Doupnik, Ph.D.

Committee Member

David Morgan, Ph.D.

Keywords

Arginase 1, Arginine Sensing, GPRC6A, mTORC1, Neurodegeneration, Neuroinflammation

Abstract

Alzheimer’s disease (AD) remains the most common neurodegenerative disease in the central nervous system (CNS), with amyloidosis and tauopathy as their two main hallmarks. Typical AD pathologies include cerebral plaques deposited by amyloid-β, neurofibrillary tangles aggregated by tau, and neuroinflammation caused by activated brain myeloid cells. A critical theme is centered on impaired brain metabolism. Emerging evidence showed that impaired arginine metabolism was a novel biomarker pathway for AD. The manipulation of arginine metabolism by a critical enzyme arginase 1 (ARG1) in neurons indicated therapeutic benefits in alleviating tau pathology. Balanced cellular proteostasis was governed by the mechanistic target of rapamycin (mTOR) pathway, which senses the activation signal by nutrients, such as arginine. Accumulating evidence reported elevated mTOR signaling in AD. It remains unclear if and how modulating arginine metabolism by ARG1 in brain myeloid cells impacts amyloidosis associated with microglial metabolic fitness and functions. Meanwhile, it’s unknown if arginine sensing machinery contributed to the increased mTOR signaling in AD and if it’s beneficial for improving AD pathologies by modulating potential novel extracellular arginine sensors, such as G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Herein, to determine the impact of reducing myeloid ARG1 to amyloid pathology, we generated a new AD amyloidosis mouse model with insufficient ARG1 in myeloid cells using lysozyme M (LysM) promoter, and performed comprehensive assessments including immunohistochemistry, biochemistry, behavioral analysis, and targeted transcriptome analysis. To examine the arginine sensing pathways associated with mTOR signaling in AD, we analyzed human AD brain samples, a mouse model of tauopathy, and several different in vitro cell models overexpressing tau. In this dissertation, we observed myeloid ARG1 insufficiency increased amyloid pathology, and impaired microglial phagocytosis machinery associated with mTOR pathway. Furthermore, transcriptomic analysis identified myeloid ARG1 insufficiency promoted microglial signatures that are non-phagocytic and positively correlated with amyloid deposition. In addition, we found human AD brains and tauopathy mouse brains showed elevated arginine sensors and arginine sensing associated mTOR signaling, which GPRC6A served as a critical arginine receptor to activate mTOR in AD. Overall, these findings strongly suggest that proper arginine metabolism controlled by the ARG1 enzyme and arginine sensing regulated by the GPRC6A receptor are critical to overall brain metabolism in AD. Therefore, future therapeutics targeting ARG1 and GPRC6A hold great promise in mitigating neurodegenerative diseases like AD.

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