Age-related illnesses present major public health challenges due to their increasing prevalence, associated disability and current lack of effective therapies. The broad, long-term goal of this project is to understand the role of aging physiology, and particularly age-related synaptic dysfunction, in the pathogenesis of Alzheimer's disease (AD). AD is the most common cause of neurodegeneration and dementia, and age is the single greatest risk factor for AD. Several features of AD, including the monogenic nature of causative mutations and the well-defined clinical (memory impairment) and pathological changes (age-dependent degeneration of cortical neurons), offer promising avenues to study the basic biology of aging and to uncover mechanisms of pathological aging. Mutations in the amyloid precursor protein (APP) and presenilins (PS1 and PS2) are the major causes of familial AD (FAD);thus, elucidation of the pathogenic mechanisms triggered by these mutations should provide important insights into AD pathogenesis in particular and pathological aging in general. However, the molecular and cellular mechanisms contributing to AD remain poorly understood, and new models and approaches would greatly enhance efforts to understand the interplay between aging and disease mechanisms. In this application, three investigators with complementary and overlapping expertise join forces to develop and implement interdisciplinary tools focused on advancing our understanding of aging physiology in AD pathogenesis. The guiding hypothesis of our proposal is that synaptic dysfunction plays a causal role in age-dependent neuronal degeneration in AD. This hypothesis derives from our prior work demonstrating that conditional PS inactivation in the adult mouse brain causes synaptic dysfunction followed by age-dependent neurodegeneration characterized by many of the neuropathological hallmarks of AD. Moreover, further investigations of the synaptic dysfunction caused by PS deficiency revealed a specific impairment in presynaptic neurotransmitter release. Here we propose a series of complementary studies designed to test the roles of impaired PS and presynaptic function in age-dependent synaptic and neuronal degeneration. We further propose to develop experimental tools that will facilitate these studies, including generation of several new mouse models, novel genetic and optogenetic approaches to manipulate synaptic transmission in the mouse hippocampus, high-resolution fluorescence imaging of synaptic terminals in mouse models, establishment of FAD patient-specific iPS cells, and combined electrophysiological and imaging methods for analysis of presynaptic neurotransmitter release. Accomplishment of these goals will expand significantly the experimental arsenal available to probe the mechanisms of pathological aging in neurological disease. Mechanistic insights gained from our studies promise to advance our understanding of the role of aging physiology, and particularly age-related synaptic dysfunction, in neurodegeneration and cognitive decline, possibly pointing the way to new therapeutic approaches.
Alzheimer's disease (AD) is a common and devastating age-related illness for which there is no effective disease-modifying therapy. Improved understanding of the pathogenic mechanisms in AD promises to provide important insights into the role of aging in neurodegeneration and dementia, possibly pointing to new therapeutic avenues. This application from a team of investigators with complementary expertise proposes to develop and implement novel interdisciplinary tools focused on synaptic dysfunction and aging physiology in the pathogenesis of AD.
