Research Project
10195947
Dementia is a progressive, incurable, and uniformly fatal neurodegenerative disorder. Alzheimer?s disease (AD) is the primary cause of progressive dementia, followed by Lewy body dementia and frontotemporal dementia (FTD). The prevalence of AD and related dementias (ADRD) increases with age. With increasing longevity worldwide, the societal impact of ADRD will become more severe. A common, pathological hallmark of these dementias is the accumulation of abnormal ?-synuclein (?-syn), amyloid-? (A?) and tau species in and around affected tissues, leading to neuronal cell death. Although treatments are available to relieve some ADRD symptoms, current therapeutic interventions for ADRD are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. It has been suggested that discovery of a molecule that could prevent or reverse neurotoxic forms of ?-syn, A? and tau species such as oligomers and fibrils could slow or reverse ADRD disease. We recently identified Fas Apoptosis Inhibitory Molecule (FAIM), which can prevent and reverse pathogenic ?-syn, A? and tau species in vitro, suggesting that FAIM might fulfil a key role in antagonizing these pathogenic species in vivo. Furthermore, it has been reported that FAIM expression is reduced in the hippocampal samples from AD patients, especially in the late BRAAK stages, further suggesting a role in disease. In spite of compelling data on FAIM activity in vitro and of low FAIM expression in AD brain, whether and to what extent FAIM is involved in the prevention/clearance of the neurotoxic proteins in neurons, and what regulates FAIM expression in neurons still remains unexplored. The long-term goal of this study is to gain a greater comprehension of basic molecular mechaisms of FAIM function/expression in ADRD, which may enable development of new preventive or disease-modifying strategies that eliminate neurotoxic ?-syn, A? and tau species in ADRD patients to slow or reverse ADRD symptoms. Specifically, the immediate goals of this proposal are to identify factors regulating FAIM expression in cortical neurons derived from human induced pluripotent stem cells (iPSCs). We will further determine whether and to what extent FAIM-deficiency or FAIM-overexpression affects the levels of pathogenic tau species using FAIM-deficient or FAIM-overexpressing cortical neurons. The proposed study will determine for the first time whether FAIM expression levels are associated with ADRD pathogenesis through modifying the formation of pathogenic protein species in addition to the molecular mechanism of human FAIM gene regulation in neurons. This work has the potential to add a new layer of understanding in the pathophysiology of ADRD onset and progression, which might be associated with FAIM expression and its regulators. This will provide new insights into the interrelationship among FAIM expression and its regulators, protein oligomerization/fibrillization, and the ADRD pathogenesis.
