Role of VGF in Alzheimer’s Disease Pathogenesis and Progression
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.
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