Brain-Derived Neurotrophic Factor (BDNF) is expressed at moderate levels in adult brain where there is evidence that it promotes survival and growth of certain neuronal populations. BDNF levels are altered in the aged human brain and there has been considerable discussion of the possibility that impairments in the production of the neurotrophin contribute importantly to the development of age-related pathologies, including those associated with Alzheimer's disease (AD). The present proposal addresses this idea using newly developed cultured slice models that incorporate factors relevant to three of the cardinal features of AD: intraneuronal neurofibrillary tangles, amyloid induced toxicity/inflammation, and deterioration of forebrain cholinergic projections. The proposed work will test the hypothesis that BDNF will (a) reduce tangle formation, (b) protect against amyloid toxicity, and (c) enhance the anatomy and physiology of the cholinergic inputs to hippocampus. A secondary objective is to determine if up-regulation of endogenous BDNF levels reproduces the effects of exogenous BDNF on the three target systems just noted. The objectives will be pursued via five Specific Aims.
Aim One tests if changes in BDNF expression occur in advance of tangle formation in a cultured slice model.
Aim Two tests if infusions of BDNF, at concentrations shown in other components of the Program Project to have important physiological effects, slow the development of tangles.
Aim Three addresses the idea of using pharmacologically elevated levels of endogenous BDNF as a substitute for infusions of exogenous neurotrophin in the attempt to reduce tangle formation. Positive modulators of AMPA-type glutamate receptors ('ampakines') will be used in this study in the same manner as they are employed in the other sections of the Program Project.
Aim Four tests if BDNF reduces (a) the uptake of amyloid peptide (Abeta1-42) into pyramidal neurons in hippocampal field CA1 and (b) the inflammatory and toxic responses that follow uptake.
Aim Five uses a co-culture preparation to test if BDNF increases the cholinergic innervation of hippocampus arising from the septum. Whether BDNF's actions on the septal projections extend to cholinergically-driven rhythms (beta-rhythms) will also be tested. These experiments will provide a test of the hypothesis that BDNF levels have important influences on the cellular processes that generate characteristic features of Alzheimer's disease. In addition, they will generate data needed to evaluate the general idea of using pharmacological up-regulation of the neurotrophin as a therapeutic strategy. Both points are central to the other components of the Program Projects and certain of the above summarized Aims represent collaborative experiments with other PIs in the program.
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