Facilitation of the Brain Hepatocyte Growth Factor/ C-Met Receptor System: A New Approach to Treat Alzheimer’s Disease?

Review Article

Austin J Clin Neurol 2016; 3(1): 1086.

Facilitation of the Brain Hepatocyte Growth Factor/ C-Met Receptor System: A New Approach to Treat Alzheimer’s Disease?

Wright JW*, Kawas LH and Harding JW

Departments of Psychology, Integrative Physiology and Neuroscience, Washington State University, USA

*Corresponding author: John W. Wright, Department of Psychology, Integrative Physiology and Neuroscience, Washington State University, P.O. Box 644820, Pullman, WA 99164-4820, USA

Received: March 30, 2016; Accepted: May 13, 2016; Published: May 15, 2016


Alzheimer’s disease (AD) is a major neurodegenerative disorder presently without adequate treatment that is increasing in frequency as life expectancy increases. 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 reasonably large size, inability to penetrate the blood-brain barrier (BBB), and the high cost of synthesis. This review focuses on one over looked neuro trophin, hepatocyte growth factor (HGF) that acts via the Type 1 tyrosine kinase receptor c-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 (Ang IV)-based analogs including Nle¹-AngIV, Dihexa and others stimulate HGF dimerization which is a prerequisite to binding at the c-Met receptor. 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.

Keywords: Alzheimer’s disease, Angiotensin IV, Nle¹-Angiotensin IV, Dihexa, AT4 receptor subtype, Hepatocyte growth factor, c-Met receptor


Aβ: Amyloid Beta Protein; ACE: Angiotensin Converting Enzyme; Ach: Acetylcholine; ACSF: Artificial Cerebrospinal Fluid; AD: Alzheimer’s Disease; Ang: Angiotensin; Ang(3-7): Angiotensin II(3-7); AngI: Angiotensin I; AngII: Angiotensin II; AngIII: Angiotensin III; AngIV: Angiotensin IV; AP-A: Aminopeptidase A; AP-N: Aminopeptidase N; ARBs: Angiotensin Receptor Blockers; AT1: Angiotensin Receptor Subtype 1; AT2: Angiotensin Receptor Subtype 2; AT4: Angiotensin Receptor Subtype 4; BBB: Blood- Brain Barrier; BDNF: Brain-Derived Neurotrophic Factor; Carb-P: Carboxypeptidase P; CBF: Cerebral Blood Flow; CIP: Chromatin Immunoprecipitation; c-Met: Met Type 1 Receptor Tyrosine Kinase; D: Aspartate; ERK: Extracellular Signaling-Regulated Kinase; F: Phenylalanine; FDA: Federal Drug Administration; H: Histidine; HGF: Hepatocyte Growth Factor; HIV: Human Immunodeficiency Virus; I: Isoleucine; Ile: Isoleucine; K: Lysine; L: Leucine; LTP: Long-Term Potentiation; LVV-H7: Leucine-Valine-Valine- Hemorphin-7; MAPK: Mitogen Activated Protein Kinase; MCI: Mild Cognitive Impairment; N: Asparagine; NGF: Nerve Growth Factor; Nle: Norleucine; NMDA: N-Methyl-D-Aspartate; NO: Nitric Oxide; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; NT3: Neurotrophin-3; NT4: Neurotrophin-4; P: Proline; Phe: Phenylalanine; ψ: CH2-NH2; PO: Propyl Oligopeptidase; Pro: Proline; P13K: Phosphatidylinositol 3-Kinase; R: Arginine; RAS: Renin- Angiotensin System; SK: Scatter Factor; SPH: Serine Proteinase Homology; Tyr: Tyrosine; V: Valine; Y: Tyrosine


Alzheimer’s disease (AD) is characterized by elevated levels of amyloid plaques and neurofibrillary tangles that predispose progressive neuron losses in memory related structures including neocortex, piriform cortex, hippocampus and the nucleus basalis of Meynert [1,2]. AD currently afflicts approximately 5.3-6 million Americans with annual treatment and care costs estimated at $70-100 billion [3,4]. These patients respond only marginally to presently available FDA approved drugs [5,6]. In the absence of a breakthrough in treatment the number of AD patients is predicted to reach 16 million in the U.S. by mid-century with associated health care costs in excess of $500 billion [4,7]. Such costs will cripple our health care system. The goal of providing an effective treatment for AD has been elusive due to the complexity of the disease process and resulting inability to identify reliable biomarkers. In addition, AD diagnostic indicators are present in other clinical conditions including vascular disease, frontotemporal dementia, Parkinson’s disease and HIV infection induced dementia, as well as normal aging [8-11]. These considerations make drug development to treat AD a very challenging task. A treatment designed to delay the onset of symptoms would prolong and maintain the patient’s quality of life and significantly reduce health care costs. De la Torre [12] has calculated that postponing the onset of AD by 5 years could reduce patient numbers by upwards of 50%. Recently it has been reported that the presence of two positive biomarkers for AD, β-amyloid and neuro degeneration, and the use of in vivo amyloid imaging agents, offer pre-diagnostic predictive value regarding the trajectory of cognitive change [13,14]. These findings promise to be of major importance regarding diagnosis but not prevention of AD.

Current drugs to treat Alzheimer’s disease

Available FDA approved drugs to treat AD fall into two major classes (Table 1): 1) Namenda (memantine HCl) acts as an N-methyl-D- aspartate (NMDA) receptor antagonist designed to limit glutamate excitotoxicity and resulting neuronal damage [15-17]. Namenda has shown positive results in some patients particularly if given in combination with acetylcholinesterase inhibitors [5,6]. 2) Cholinesterase inhibitors such as Razadyne, Exelon, Cognex and Aricept disrupt the degradation of acetylcholine (Ach) thus extending the half-life and availability of this neurotransmitter acting at central cholinergic muscarinic and nicotinic receptors. Additional treatment approaches being vigorously pursued include monoclonal antibodies designed to attenuate and block the production and deposition of insoluble amyloid β (Aβ) protein fragments resulting from amyloid precursor protein proteolysis. It is suggested that dysfunction between Aβ production and clearance causes damaging accumulations of cellular Aβ, coupled with hyper phosphorylation of neuronal tau protein resulting in neurofibrillary tangle formation [18-20]. Antiinflammatories and anti-oxidants are also being tested including nonsteroidal anti-inflammatory drugs (NSAIDs, eg. naproxen, rofecoxib, ibuprofen, indomethacin, tarenflurbil, diclofenac/misoprostol), luteolin, ferulic acid to protect against neurotoxicity [21-24].