There are more than 70,000 Oklahomans who suffer from Alzheimer's disease (AD) and it is estimated that 96,000 patients will be diagnosed with AD by 2025 in Oklahoma. Cognitive decline in Alzheimer's disease is thought to be the result of disturbed neuronal communication due to synaptic dysfunction. Aggregated amyloid beta protein accumulates in AD, a process dependent on synaptic activity. In this series of studies we investigate how synaptobrevin1, an essential synaptic protein, regulates amyloid secretion. Maintaining physiological synaptic function while reducing amyloid secretion may provide a breakthrough to design effective therapies that halt progression of dementia in Alzheimer's disease.
Funded through the Oklahoma Center for the Advancement of Science and Technology
With advanced age several aspects of brain function are known to be impaired, including processing speed, inductive reasoning, and spatial learning and memory. For aging subjects that experience impairment of these functions, the reduction in cognitive ability can be disabling and diminish both health-span and independence. It is thought that the primary cause of cognitive impairment in Alzheimer’s disease is the accumulation of amyloid plaques and neurofibrillary tangles. Amyloid production is known to strongly correlate with synaptic activity. However, the regulation of specific pathological steps leading to excessive amyloid production and amyloid secretion are unknown and the absence of key mechanistic data on molecular pathways for these processes impedes the development of effective therapeutic interventions. Therefore new approaches to solve AD etiology are urgently needed. This application is designed to address these issues. PI discovered in his previous work that function of synaptobrevins/VAMPs was to organize synaptic vesicular recycling, which finding was later confirmed by independent groups. Based on this and other published data and a series of specific preliminary studies the applicants hypothesize that expression levels of synaptobrevin/VAMP1, a synaptic vesicle protein, regulates amyloid production in AD and contributes to age–related cognitive impairment. To test this hypothesis two genetically modified mouse lines have been developed: First, a knock-out of VAMP1 that mimicks the AD related decreased risk phenotype in the lower expression level of this key protein will be investigated. This model will be used to analyze regulation of synaptic function and amyloid production. Second, a combination of the VAMP1 mouse model with a transgenic AD model expressing human amyloid precursor protein that mirrors various pathological features of AD. This mouse model will provide valuable data about the significance of synaptobrevin/VAMP1 in amyloid production and as a possible prevention method to maintain cognitive function in AD. Two aims are proposed with studies that include behavioral testing of learning and memory, biochemical assays for molecular changes with age and AD progression, electrophysiological experiments and live fluorescence microscopy to quantify synaptic release and plasticity. After completion the results from the proposed experiments have the potential to fill a major knowledge gap in our understanding regarding cognitive impairment in AD and significantly move the field forward by providing novel animal models and validating a new molecular target for future therapeutic interventions.