Roles of TREM2 and Protein Prenylation Pathways in Brain Aging and in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder, affecting millions of lives without a cure. While the molecular mechanism of AD remains obscure, genome-wide association studies (GWAS) have identified a great number of AD risk genes, enlightening the molecular pathways that contribute to the pathogenesis of AD. One of the high AD risk genes being identified is the loss-of-function variants of triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 is a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. A large number of studies have investigated the impact of TREM2 deficiency in the pathogenic process of AD. However, the role of TREM2 in shaping neuronal and cognitive function during normal aging is underexplored and is the focus of the first part of my dissertation. The results show that loss of Trem2 affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging. The second part of the dissertation focuses on the role of protein prenylation in regulating synaptic/cognitive function. Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic functions and cognition in the nervous system. Emerging evidence suggests that upregulation of protein prenylation contributes to the pathogenesis of AD. Two enzymes, farnesyltransferase (FT) and geranylgeranyl transferase type I (GGT) are essential for the prenylation process. Genetic reduction of FT or GGT ameliorates neuropathology but only FT haplodeficiency rescues cognitive function in transgenic mice of AD. A follow-up study showed that systemic or forebrain neuron-specific deficiency of GGT leads to synaptic and cognitive deficits under physiological conditions. Whether FT plays different roles in regulating neuronal functions and cognition is assessed in the current dissertation. The results show that physiological levels of FT and GGT in neurons are essential for normal synaptic/cognitive functions and that the prenylation status of specific signaling molecules regulates neuronal functions. The third part of the dissertation focuses on the role of downstream targets of FT in AD. As an exclusively farnesylated target, the small GTPase H-Ras governs essential cellular functions and has been studied extensively in cancers. Despite the findings that H-Ras regulates synaptic function and both upstream and downstream signaling of H-Ras have been implicated in AD, the role of H-Ras in AD pathogenesis has not been explored previously. The results of the present dissertation research reveal that genetic deletion of H-Ras rescues memory deficits, reduces amyloid deposition, and protects against dendritic spine loss near amyloid plaques in transgenic AD mice, suggesting H-Ras as a potential therapeutic target for AD in addition to cancers. Taken together, the current dissertation elucidates the role of TREM2 during physiological aging, portrays the function of farnesylation at hippocampal synapses, and characterizes the role H-Ras in the pathogenesis of AD. Findings from this dissertation provide novel insights into the cellular and molecular mechanisms underlying the complex neuronal role of TREM2 in aging and its implications for TREM2-based treatments in AD, and identify farnesylation and its downstream signaling molecules as potential therapeutic targets for AD.