Christopher William - US grants

DESCRIPTION (provided by applicant): Synaptic degeneration plays a critical role in the cognitive decline of patients with Alzheimer disease (AD). Recent in vitro data suggest that the Amyloid Precursor Protein (APP)-derived peptide, Abeta, drives synaptic degeneration through the activation of signaling pathways that regulate synaptic plasticity;however, in vivo evidence of this is limited. In addition, roles have been proposed for APP and Abeta in neurite pruning and synaptic plasticity outside of the context of disease, however, these hypotheses are similarly difficult to assess in the intact brain. The developing visual cortex offers a unique model in which to test perturbations of synaptic plasticity. In juvenile mice, a critical period of increased synaptic plasticity exists in which the loss of vision from one eye triggers cortical rewiring that results in enhanced responses to visual input from the active eye as well as weakening of responses from the inactive eye in a process termed ocular dominance plasticity (ODP). This process requires pathways involved in adult plasticity, including regulation of NMDA receptor activity and regulation by GABAergic inhibitory circuitry, suggesting that the developing visual system may provide a powerful, tractable model in which to study the effects of Abeta on plasticity in vivo. Preliminary evidence reveals that transgenic mice that express elevated levels of Abeta exhibit a loss of critical period ODP, providing further evidence that exposure to elevated levels of Abeta interferes with synaptic plasticity and normal function. Through biochemical analyses and histological approaches, the mechanism by which this plasticity deficit occurs will be studied. Using this approach, roles for APP and Abeta in normal synaptic plasticity will also be explored. Lastly, adult ODP has been demonstrated in mice, though the process is physiologically distinct and less well characterized. The hypothesis that Abeta accumulation blocks adult ocular dominance plasticity will be tested and the results compared to those obtained during the juvenile period. The goals of this study are to define the role of APP and Abeta in regulating synaptic plasticity, gain insight into the underlying mechanism, and test whether this effect can be pharmacologically modulated- all using a robust, in vivo model of synaptic plasticity. The candidate is an MD/PhD, trained in anatomic pathology and neuropathology, whose long term goal is to study the molecular pathways responsible for the establishment of the functional nervous system and to understand the roles that these pathways play in the decline of function in neurodegenerative disease. During the course of this research sponsored by Dr. Bradley Hyman, MD, PhD, at Massachusetts General Hospital (MGH), the most current genetic, molecular, physiologic imaging and histological approaches will be used to examine the action of APP and Abeta at the synapse. These studies will allow the candidate to acquire the skills necessary to advance to a career as an independent investigator. During the proposed course of mentored scientific training, the candidate will also continue to develop the clinical skills required to become an academic neuropathologist through additional training at MGH. PUBLIC HEALTH RELEVANCE: The research program described in this proposal will provide insight into the nature of the synaptic dysfunction thought to play a critical early role in Alzheimer disease. In addition to studying the effects of the disease process on synaptic function in the intact brain, this approach also provides a novel system in which to test therapeutic approaches that attempt to restore synaptic function. These studies promise to facilitate the identification and validation of potential drug targets and to provide an in vivo system in which to test pharmacologic approaches to treatment, ultimately to aid in the development of new therapies to reduce the burden of Alzheimer disease on patients, families and society.