Aging and age-related degenerative diseases have received increased attention due to their socioeconomic impact in the western world. Even though mutations have been identified for Alzheimer's disease (AD), we still do not know which factors regulate this neurodegenerative disease. AD is signified by a marked loss of cholinergic and noradregeneric innervation of the hippocampal formation and a decrease in nerve growth factor (NGF) levels in the basal forebrain. A lack of retrograde NGF transport or release may lead to the cholinergic loss, since NGF levels are actually increased in the hippocampal formation. Data suggest that incorrect processing of amyloid precursor protein (APP) plays a significant role in AD, since it has been shown that most known mutations in AD are directly or indirectly linked to levels or processing of APP. Recently, a direct relationship between APP and NGF has been shown in vitro. However, no in-vivo models have been designed to explore this relationship in intact brain tissue. In the last five years, we used intraocular and intracranial transplants into younger and aged rats to explore factors that are related to noradrenergic neuroplasticity in the hippocampal formation. We were able to demonstrate that aged noradrenergic neurons had a strong endogenous ability to regenerate, and we also investigated several factors that affected regeneration in the target tissue. We would now like to continue this work in the area of cholinergic neuron regeneration and explore similar target-related factors. The specific questions to test the overall hypothesis are: 1) Do NGF levels in the hippocampus and basal forebrain correlate with the level of memory impairment in aged, behaviorally characterized rats? 2) Is NGF release related to memory impairment in aged rodents or by cholinergic innervation in intraocular double transplants? 3) Are levels of APP correlated with the degree of NGF release, the NGF tissue levels, and/or the degree of memory impairment in aged, behaviorally characterized rats? These specific questions are aimed to assess the overall hypothesis that APP and NGF participate in spatial memory and the functional maintenance of cholinergic neurons. If the biological mechanism for the observed NGF loss in basal forebrain of AD patients can be defined, future drug intervention may concentrate on either NGF release or NGF transport for this disease.
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