The success of basic neurobiological research depends upon the availability of suitable simple systems to investigate complex problems. AD is clearly a complex disorder which impacts upon multiple systems. One of the most vulnerable and earliest systems to be affected is the entorhinal system. This system embodies most of the key issues in the disease. We propose to develop the entorhinal hippocampal system as a simple system where detailed investigations of defined circuity can be performed The proposed research is multidisciplinary and has its roots in the theme of synaptic plasticity which indicates occurs in AD. In the dentate gyrus of the AD brain we proposed to investigate the sprouting response of the various afferent and the behavior of receptor particularly the n-methyl-d-aspartate (NMDA) receptor. We will compare response in animals with entorinal lesions to those in the AD brain with entorhinal pathology. We suggest that the trophic status of the vulnerable neurons in the circuit depends on the balance between NMDA receptor function (its trophic versus excitotoxic potential) and polypeptide neurotrophic factors levels, receptors, and integrity of second messenger responses). Detailed investigations will be carried out by vivo and in vitro in a new culture system of dentate granule-entorhinal neurons. In the course of AD neurons die slowly from within a population creating fractional cell loss. In order to define the accuracy of animal models we will develop a new method to create functional cell loss in the entorhinal cortex and hippocampus. We will use this to better define the plastic response, to analyze behavioral consequences to various degrees of cells loss, and to evaluate new therapeutic approaches derived from our molecular analyses.
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