The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease

Article type: Review Article

Authors: Wright, John W.^{a; b; c; d; *} | Harding, Joseph W.^{a; b; c; d}

Affiliations: [a] Department of Psychology, Washington State University, Pullman, WA, USA | [b] Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA | [c] Program in Biotechnology, Washington State University, Pullman, WA, USA | [d] M3 Biotechnology, Inc., Seattle, WA, USA

Correspondence: [*] Correspondence to: John W. Wright, PhD, Department of Psychology, Washington State University, P.O. Box 644820, Pullman, WA 99164-4820, USA. Fax: +1 509 33 5043; E-mail: [email protected].

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease increasing in frequency as life expectancy of the world's population increases. There are an estimated 5 million diagnosed AD patients in the U.S. and 16 million worldwide with no adequate treatment presently available. New therapeutic approaches are needed to slow, and hopefully reverse, disease progression. This review summarizes available information regarding an overlooked therapeutic target that may offer a treatment to slow and hopefully halt AD, namely the hepatocyte growth factor (HGF)/c-Met receptor system. Activation of the c-Met receptor stimulates mitogenesis, motogenesis, morphogenesis, the ability to mediate stem cell differentiation and neurogenesis, and protects against tissue insults in a wide range of cells including neurons. This growth factor system has recently been shown to induce dendritic arborization and synaptogenesis when stimulated by a newly developed angiotensin-based analogue, N-hexanoic-Tyr-Ile-(6) amino hexanoic amide (Dihexa). This small molecule was derived from the pre-prototype molecule Nle1-angiotensin IV and has shown promise in facilitating the formation of new functional synaptic connections and augmenting memory consolidation in animal models of AD. Dihexa is a first-in-class compound that is orally active, penetrates the blood-brain barrier, and facilitates memory consolidation and retrieval. This angiotensin-based small molecule may be efficacious as a treatment for AD.

Keywords: Alzheimer's disease, angiotensin IV, AT₄ receptor subtype, c-Met receptor, Dihexa, hepatocyte growth factor, Nle¹-Angiotensin IV

DOI: 10.3233/JAD-142814

Journal: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 985-1000, 2015