Small molecule activation of the neurotrophin hepatocyte growth factor to treat Alzheimer disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neuron loses in memoryrelated brain structures. Five drugs have been approved by the FDA to treat Alzheimer's disease; however, these drugs have failed to modify or significantly slow disease progression. New therapies are needed to delay the course of this disease and hopefully prevent further neuron losses. This review describes available AD drugs and several novel approaches presently being investigated. We next describe relevant biomarkers and urge greater research interest in the potential utilization of neurotrophic agents to treat AD. Neurotrophins such as nerve growth factor, brain-derived neurotrophic factor and hepatocyte growth factor (HGF) are capable of stimulating dendritic arborization, synaptogenesis, stem cell differentiation, neurogenesis, and decreases in neuroinflammation, oxidative stress-induced damage and neurotoxicity due to a wide range of cellular insults. We present the strategy of utilizing small molecule analogs specifically designed to penetrate the blood-brain barrier and facilitate dimerization and activation of the HGF/Met receptor system. These molecules have been shown to encourage the formation of new functional synaptic connections, induce long-term potentiation and augment memory consolidation and retrieval in animal models of AD. Such molecules may be appropriate for use at the first indication of mild cognitive impairment, and perhaps prophylactically in those individuals who are most likely to develop dementia due to genetic, health, behavioral and lifestyle predisposing factors.