AD-focused Administrative Supplement for NIH Grant Neuroprotective Role of Sirt6 in Glaucoma

摘要

ABSTRACT Alzheimer's disease (AD) is the sixth-leading cause of death in the United States that significantly impairs patients' lifespan. In addition to dementia, visual impairments are very prevalent in AD patients and significantly affect their life quality, cause behavioral challenges and even put safety risks to AD patients. Meanwhile, poor vision is a contributing factor to dementia. Nevertheless, to date, few studies have been conducted to address visual impairments in AD. Considering aging is the best known risk factor for AD, strategies that can modulate aging process may have profound effects for AD management. One of the major focuses in the parent award is to determine whether boosting expression of Sirt6, which is a key anti-aging molecule, prevents mitochondrial dysfunction in retinal ganglion cells (RGCs) and therefore protects against RGC injury and optic nerve degeneration in mouse models of glaucoma induced by elevated intraocular pressure. In this application, we will conduct experiments to generate preliminary data to determine if Sirt6 also plays a neuroprotective role in preventing the injury of RGCs and their axons in AD via inhibition of mitochondrial dysfunction. In the future, based on pilot data from this work, we will further determine cellular and molecular mechanisms by which Sirt6 prevents RGC injury and axonal degeneration in AD, and investigate if pharmacologic activation of Sirt6 prevents vision loss in AD; moreover, we will test if boosting Sirt6 expression and activity alleviates behavioral deficits and neurodegeneration in the brain during AD, given that the retina is an extension of the brain and shares many pathophysiological mechanisms of the brain. Overall, this pilot project and its subsequent future studies will provide important new knowledge that may guide the development of novel therapies for AD.