The entorhinal cortex (EC) is one of the earliest sites of neuronal loss in Alzheimer's disease (AD), and degeneration of this structure likely leads to the short-term memory loss that is a hallmark of AD. Brain-derived neurotrophic factor (BDNF) and its receptor trkB are present in the entorhinal cortex and hippocampus, exerting important roles in synaptic plasticity and neuroprotection. Notably, levels of BDNF decline in the EC in AD. Recent findings in our laboratory suggest that BDNF delivery may broadly protect and stimulate neurons of the entorhinal cortex in rodent models:1) BDNF prevents cell death in the EC following lesions of the perforant path in rats.2) BDNF significantly reduces direct Aß toxicity in dissociated cell cultures of rat primary entorhinal cortical neurons.3) In aged rats, BDNF reverses both age-related declines in spatial memory and restores levels of ERK activation to levels of young rats.4) In transgenic mice co-expressing two mutant forms of the APP gene (Swedish/Indiana), BDNF significantly improves spatial learning and memory and improves ERK activation.This proposal will determine whether BDNF also exhibits potent neuroprotective effects in the non-human primate brain. Specifically, we will study two models in rhesus monkeys: entorhinal cortical neuron death after perforant path lesions, and age-related cognitive decline. Should we find that BDNF treatment has neuroprotective effects in these models on both cell survival and cognitive function, a rationale for possible future human studies of BDNF in early AD would be established. Experiments in this study will utilize in vivo gene delivery of BDNF to deliver growth factors safely and in a sustained fashion.