Small Molecule AngIV-based Analogs to Treat Alzheimers Disease

Alzheimer’s disease (AD) patients are presently without adequate treatment thus new therapeutic approaches are needed to slow and hopefully reverse disease progression. Neurotrophic agents such as nerve growth factor and brain-derived neurotrophic factor have received research attention concerning their potential to treat AD but have not progressed to clinical trials due to their large size, inability to penetrate the blood-brain barrier (BBB), and the high cost of synthesis. This review focuses on one over looked neurotrophin, hepatocyte growth factor (HGF) that acts via the Type 1 tyrosine kinase receptor Met to mediate stem cell differentiation, synaptogenesis, neurogenesis, and protect against tissue insults in a wide range of cell types including neurons. We have determined that the brain angiotensin and HGF/c-Met systems interact in such a way that angiotensin IV (AngIV)-based analogs including Nle1-AngIV, Norleual-AngIV, Dihexa, and others influence HGF dimerization which is a prerequisite to binding at the Met receptor. Several of these analogs have shown the ability to facilitate the formation of new functional synaptic connections in hippocampal slices, promote neurogenesis, and augment memory consolidation and retrieval in animal models of AD. This family of compounds represents a new class of drugs with lead candidates that are orally active, penetrate the BBB sufficiently to reach therapeutic concentrations, and reverse memory deficits seen in animal models of dementia.


John W Wright and Joseph W Harding

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