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Mechanisms of neurotrophin-improved cognition in aging

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Aging and Alzheimer's disease are correlated with a progressive loss of cognitive function. Even though a significant increase in resources and research emphasis have been spent on investigating memory loss, it is still not known which biological events in the brain that lead to age-related cognitive impairment. Studies have demonstrated that altered function of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may lead to age-related cognitive impairment. Likewise, many investigators believe that faulty processing of the amyloid precursor protein (APP), leading to production of the deadly beta-amyloid, is the culprit in age-related neuronal loss and cognitive dysfunction, especially in Alzheimer's disease. Amyloid is formed by gamma-secretase mediated cleavage of the APP pre-protein. In the past grant period we investigated effects of NGF upon cholinergic neurotransmission during aging. We would like to continue this work, and expand our focus to include BDNF, since this growth factor has been shown to be involved in memory. We propose a hypothesis that NGF and BDNF play important roles in neurotransmission in the hippocampus. In addition, we postulate that this neurotrophic influence is altered by APP and/or amyloid processing during aging, leading to lost neurotrophic function and, eventually, memory loss. In order to investigate this hypothesis we propose the following specific aims:

1. To determine if release, uptake, or retrograde transport of BDNF and/or NGF are altered in aged animals. 2. To determine if amyloid synthesis and/or gamma-secretase activity is altered in aged rodents, and if so: if this is correlated with age-related memory impairment or neurotrophic loss.

The overall goal is to determine if NGF and BDNF activity is altered during aging because of altered release, uptake, or transport, and also to determine if this altered neurotrophic activity is related to alterations in amyloid-enzyme activities. We hope that these findings will ultimately lead to better treatment paradigms for patients with neurodegenerative diseases, in particular Alzheimer's disease, and provide a more mechanistic base for knowledge regarding this disease.
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