Dementia, whether resulting from Alzheimer's disease, stroke, or other neurodegenerative disorders, results from damage to nerve cells (neurons) leading to their death or a with other neurons. Survival of neurons, the maintenance of connections, and even the ability to generate new connections and produce new neurons from stem cells found in the brain is under the control of a family of proteins called neurotrophic factors. The greatest difficulty preventing their clinical use is the general inability of large proteins, like neurotrophic factors, to move from the blood into the brain across what is known as the blood-brain barrier (BBB). Hepatocyte growth factor (HGF), a neurotrophic factor, can dramatically stimulate connectivity among neurons, protect neurons from insults that would otherwise kill them, and induce the generation of new neurons from neural stem cells. Nevertheless, like all neurotrophic factors HGF suffers from the same inability to penetrate the brain. Recently, however, we have developed drug candidates that mimic the action of HGF and are able to penetrate the BBB. In addition these drugs are orally active and can be taken in pill form. They have been shown to reverse learning and memory deficits apparent in multiple dementia models and increase communication efficiency among neurons.The goals of this project are two-fold. First we wish to validate the utility of our lead compound, called Dihexa, in an aged rat model of age-related cognitive decline. The expectation is that Dihexa will slow or halt the deterioration of cognitive function and reverse cognitive deficits. Second we want to confirm Dihexa's anticipated mechanism of action by demonstrating enhanced neuronal communication, increased neuronal connectivity, improved neuronal survivability, and potentially the generation of new neurons. The long-term goal of this project, which is beyond the scope of this proposal, is to move Dihexa toward human clinical trials.