VGF as a biomarker and therapeutic target in neurodegenerative and psychiatric diseases

Abstract

Neurosecretory protein VGF (non-acronymic) belongs to the granin family of neuropeptides. VGF and VGF-derived peptides have been repeatedly identified in well-powered and well-designed multi-omic studies as dysregulated in neurodegenerative and psychiatric diseases. New therapeutics is urgently needed for these devastating and costly diseases, as are new biomarkers to improve disease diagnosis and mechanistic understanding. From a list of 537 genes involved in Alzheimer’s disease pathogenesis, VGF was highlighted by the Accelerating Medicines Partnership in Alzheimer’s disease as the potential therapeutic target of greatest interest. VGF levels are consistently decreased in brain tissue and CSF samples from patients with Alzheimer’s disease compared to controls, and its levels correlate with disease severity and Alzheimer’s disease pathology. In the brain, VGF exists as multiple functional VGF-derived peptides. Full-length human VGF1–615 undergoes proteolytic processing by prohormone convertases and other proteases in the regulated secretory pathway to produce at least 12 active VGF-derived peptides. In cell and animal models, these VGF-derived peptides have been linked to energy balance regulation, neurogenesis, synaptogenesis, learning and memory, and depression-related behaviours throughout development and adulthood. The C-terminal VGF-derived peptides, TLQP-62 (VGF554–615) and TLQP-21 (VGF554–574) have differential effects on Alzheimer’s disease pathogenesis, neuronal and microglial activity, and learning and memory. TLQP-62 activates neuronal cell-surface receptors and regulates long-term hippocampal memory formation. TLQP-62 also prevents immune-mediated memory impairment, depression-like and anxiety-like behaviours in mice. TLQP-21 binds to microglial cell-surface receptors, triggering microglial chemotaxis and phagocytosis. These actions were reported to reduce amyloid-β plaques and decrease neuritic dystrophy in a transgenic mouse model of familial Alzheimer’s disease. Expression differences of VGF-derived peptides have also been associated with frontotemporal lobar dementias, amyotrophic lateral sclerosis, Lewy body diseases, Huntington’s disease, pain, schizophrenia, bipolar disorder, depression and antidepressant response. This review summarizes current knowledge and highlights questions for future investigation regarding the roles of VGF and its dysregulation in neurodegenerative and psychiatric disease. Finally, the potential of VGF and VGF-derived peptides as biomarkers and novel therapeutic targets for neurodegenerative and psychiatric diseases is highlighted.

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease

“…Depending on the goal of the project however, this specificity of quantified species may also be a limitation of these technologies. Unlike mass-spectrometry, which can be used to flexibly identify and quantify post-translational modifications such as phosphorylation, and the presence of novel protease-cleaved fragments, such as C-terminal TDP-43 ( 27 ), or specific processed peptides such as those from amyloid-β ( 28 ) or VGF ( 29 ), antibody pair technology does not have this flexibility.…”

Neurotrophin Crosstalk in the Etiology and Treatment of Neuropsychiatric and Neurodegenerative Disease

“…VGF mRNA is widely expressed in the PNS and CNS, abundantly in the hypothalamus, consistent with known function in metabolic regulation and energy balance (Snyder and Salton, 1998;Hahm et al, 1999Hahm et al, , 2002, and in the hippocampus, in line with important roles for VGF in memory and depression-like behavior (Bozdagi et al, 2008;Lin et al, 2015Lin et al, , 2021Li et al, 2017;Jiang et al, 2019a). VGF undergoes proteolytic cleavage by prohormone convertases and proteases in the regulated secretory pathway to produce at least 12 VGF-derived peptides (Levi et al, 2004;Quinn et al, 2021). VGF-derived peptides have been reported in several CSF proteomic studies to be potential biomarkers of neuropsychiatric and neurodegenerative disorders, including MDD and AD (Bartolomucci et al, 2010;Llano et al, 2019;van Steenoven et al, 2020;Quinn et al, 2021), consistent with possible functional roles for VGF in disease pathophysiology.…”

Loss of intracerebellar heterogeneity and selective vulnerability in Spinocerebellar ataxia type 1 neurodegeneration

“…These genes include Cck and Cckbr involved in CCK (Cholesytokinin) signaling known to be protective in SCA1 and SCA2 [26][57]. Wnt signaling ( Wnt8 ) [58] and neuropeptides Vgf , and Sst (somatostatin) [59][60] have each been implicated in neuroprotection in Alzheimer’s disease, Parkinson’s disease or ALS. In addition, increased expression of genes encoding proteins with anti-inflammatory roles including neuropeptide Y receptors 1 and 5 (NPY1R and NPY5R)[61], and dopamine 2 receptor ( DRD2 ) [62][63] also indicate increased protection against pro-inflammatory changes in the anterior vermis.…”