Role of VGF in Alzheimer’s Disease Pathogenesis and Progression

Stephen Salton, MD, PhD
Icahn School of Medicine at Mount Sinai (New York, NY)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2016508S
Award Type:
Standard
Award Region:
US Northeastern
Stephen Salton, MD, PhD

Role of VGF in Alzheimer’s Disease Pathogenesis and Progression

Summary

Previous work from our lab and others has demonstrated a significant decline in the expression of the neuronal protein VGF, which is a nerve growth factor, in the brains of patients with Alzheimer’s disease (AD) and amyotrophic lateral sclerosis. Moreover, a number of biomarker studies have identified that VGF-derived peptides in the cerebrospinal fluid (CSF) are decreased in patients with AD, but not in control patients. These data indicate that decreased VGF expression in the brain and CSF is associated with neurodegenerative disease; we propose to investigate whether this decline is mechanistically involved in the pathogenesis or progression of AD. In preclinical studies, we will investigate the potential mechanisms by which VGF delays or reverses memory dysfunction and neuropathology in a mouse model of AD, and lastly will investigate whether a VGF-derived peptide could be therapeutically harnessed to suppress memory impairment in these mice. The results will provide a strong foundation for future exploration of approaches that deliver VGF and/or VGF-derived peptides to patients with AD.

Details

In preclinical studies, we will investigate the potential mechanisms by which the neuronal protein VGF, which is a nerve growth factor, and specific VGF-derived peptides delay or reverse memory dysfunction and neuropathology in a mouse model of Alzheimer’s disease (AD). Previous work from our lab and others has demonstrated a significant decline in the expression of the neuronal protein and neuropeptide precursor, VGF, in the brains of patients with AD and amyotrophic lateral sclerosis. Moreover, a number of biomarker studies have identified VGF-derived peptides in the cerebrospinal fluid (CSF) that are decreased in patients with AD, but not in control patients.

Our previous studies also show that VGF and VGF-derived peptide TLQP-62 are transiently induced after fear memory training, leading to increased BDNF/TrkB signaling, and that sequestration of hippocampal TLQP-62 immediately after training impairs memory formation. These data together indicate that decreased VGF expression in the brain and CSF is associated with neurodegenerative disease; we propose to investigate whether this decline is mechanistically involved in disease pathogenesis or progression.

We hypothesize:  (1) In patients with Alzheimer’s disease, lower brain VGF levels could, under the destructive effects of toxic Ab42 and phospho-tau accumulation, further impair synaptic integrity, and accelerate neuronal cell death; (2) VGF ablation will accelerate pathological amyloid deposits and hippocampal-based memory dysfunction in an AD mouse model, 5xFAD; and (3) overexpression of VGF or administration of exogenous VGF and/or VGF-derived peptide TLQP-62 to 5xFAD mice will delay or reverse neuropathological and cognitive dysfunction.

In Aim 1, we will identify the neuroprotective mechanisms of VGF in the 5xFAD mouse model of AD. The role of VGF downregulation or overexpression to alter the progression of neuropathological and cognitive dysfunction in 5xFAD mice will be investigated by crossing our previously characterized germline VGF knockout mice (that do not express VGF), which have memory deficits, or VGFdelta3’UTR mice that overexpress VGF and have improved memory, into the 5xFAD line. In Aim 2, we will determine the signaling pathways that are activated by VGF-derived peptide TLQP-62 in wild type and 5xFAD mice. We will investigate whether TLQP-62 modulates signaling of brain-derived neurotrophic factor (BDNF), a growth factor critical for neuronal survival and development, via its receptor TrkB. In addition we will examine synaptic plasticity, synaptic structure, and neuronal activity, to determine whether they are activated or modulated by TLQP-62 equivalently in 5xFAD as in wild type mice, using a battery of molecular, biochemical and electrophysiological techniques.

Our lab is uniquely positioned, having developed a variety of well-studied biochemical and viral reagents, antisera, and animal models, to determine whether VGF could be therapeutically harnessed to suppress memory impairment in 5xFAD mice. This project can be expected to result in a strong foundation for future exploration of approaches that deliver VGF and/or VGF-derived peptides to patients with Alzheimer’s disease.

About the Researcher

Stephen R. Salton, MD, PhD, attended the University of Pennsylvania, graduating with magna cum laude honors in biochemistry; completed the MD-PhD program at New York University; and, following an internship and residency in internal medicine at Bellevue Hospital in New York, conducted postdoctoral research in molecular neuroendocrinology at Columbia University College of Physicians and Surgeons and Mount Sinai School of Medicine. Dr. Salton has received a number of academic and scientific honors including a Medical Scientist Training Program Award, Pfizer Post-Doctoral and Scholar Awards, Pew Scholars Award in the Biomedical Sciences, Irma T. Hirschl-Monique Weill-Caulier Career Scientist Award, and NARSAD van Ameringen Investigator Award. He has held faculty positions at the Icahn School of Medicine at Mount Sinai since 1989, and currently is a tenured professor in the Departments of Neuroscience and Geriatrics. Dr. Salton’s molecular neurobiology lab investigates the mechanisms mediating neurotrophic growth factor regulation of neural development and nervous system function, impacting the understanding of depression, memory, body weight control, neuropathic pain, and neurodegeneration. He additionally plays an active role in the broader educational mission of the institution, and contributes to a number of committees at Mount Sinai that oversee its academic and teaching missions. Dr. Salton has been co-director of the Neuroscience Graduate Training Area, responsible for overseeing the administration and operation of the program since 2000. He is author of the application securing Mount Sinai’s neuroscience PhD granting program that was approved in 2007 by NYU and the New York State Education Department. Dr. Salton currently is principal investigator on two National Institutes of Health-supported T32 training programs. 

Publications

Jiang C, Lin WJ, Salton SR. Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy. J Mol Neurosci. 2019 Jul; 68(3):504-509. PubMed PMID: 30022437 PubMed IconGoogle Scholar Icon

Jiang C, Sakakibara E, Lin WJ, Wang J, Pasinetti GM, Salton SR. Grape-derived polyphenols produce antidepressant effects via VGF- and BDNF-dependent mechanisms. Ann N Y Acad Sci. 2019 May 10. doi: 10.1111/nyas.14098. [Epub ahead of print] PubMed PMID: 31074515 PubMed Icon Google Scholar Icon

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