Distribution of VGF peptides in the human cortex and their selective changes in Parkinson’s and Alzheimer’s diseases

Abstract

VGF mRNA and its precursor-derived products are selectively expressed in certain neurons and promptly respond to neurotrophins and to neural ⁄ electrical activity. Proteomic studies have previously revealed a reduction in some VGF peptides in the cerebrospinal fluid of patients affected by Alzheimer's disease and other conditions, suggesting their potential diagnostic and clinical significance. As the presence of VGF peptides within the human cortex has been somewhat elucidated, they were studied postmortem in the frontal, parietal, and temporal cortex areas of control subjects and patients affected by Parkinson's disease, and in parietal cortex samples from patients with Alzheimer's disease. We raised antibodies to the C-⁄ N-terminal portions of the proVGF precursor protein, to the TPGH and TLQP sequences and to the neuroendocrine regulatory peptide (NERP)-1, all used for enzyme-linked immunosorbent assay coupled with gel chromatography and for immunohistochemistry. In the control brain samples, the levels of TPGH and C-terminus peptides were about 130-200 and 700-2000 pmol g)1 , respectively, the N-terminus and NERP-1 peptides were less represented (about 10-30 and 4-20 pmol g)1 , respectively), and the TLQP peptides were below detection limits. Upon gel chromatography, the VGF antisera mainly revealed small molecular weight forms (i.e. about 0.8-1.3 kDa), whereas VGF immunolocalisation was found within different types of neuron in rat and bovine brain cortices. In the Parkinson's disease samples, a clear-cut decrease was revealed in the parietal cortex only, exclusively for TPGH and NERP-1 peptides, whereas in the Alzheimer's disease samples, a reduction in all of the VGF peptides was shown. The results suggest the involvement of VGF in the physiological or pathophysiological mechanisms occurring in the parietal cortex of patients with Parkinson's and Alzheimer's diseases.

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

“…Determining the mechanisms that account for preferential differences in treatment response will enable future treatment strategies to exploit alternative pathways and molecular players in subsets of patients who do not respond to conventional medications. Moreover, since VGF has diverse roles in the hippocampus, including learning and memory [1,45,46], and is associated with impaired memory and Alzheimer’s Disease [11,12,66,67], it will also be important in future studies to explore the role of the VGF SNPs in neurodegenerative diseases as has been done for Val66Met BDNF polymorphism [68,69]. …”

“…VGF (non-acronymic) is a neuropeptide whose expression is upregulated by neurotrophins including brain-derived neurotrophic factor (BDNF) in the hippocampus [1]. VGF and its peptide products [2] have largely been studied for their role in metabolic homeostasis [3,4,5,6,7], pain [8,9,10], neurodegeneration [11,12,13,14] and, more recently, neuropsychiatric disorders [15,16,17]. Several of these diseases are associated with changes in the hippocampus and despite high expression of VGF in this brain region [18,19], the role of this neuropeptide in the hippocampus is not fully elucidated.…”

VGF peptides upon osmotic stimuli: Changes in neuroendocrine regulatory peptides 1 and 2 in the hypothalamic–pituitary-axis and plasma

“…As yet there is no information on the VGF receptors which could mediate the action of these peptides into the bloodstream, and further peptidomic investigations are warranted. Moreover, since reduction in the NERP-1 content is found in the frontal cortex of Alzheimer patients (Cocco et al, 2010) where ADH is found to be reduced (Labudova et al, 1998), together with its decrease in the hypothalamus (Mann et al, 1985), possible future studies may regard the involvement of NERPs in ADH mechanisms in these patients.…”

“…The rat VGF C-terminus, TLQP, rat PGH and NERP-1 antisera were produced as previously reported (Cocco et al, 2010) while in order to obtain NERP-2 antiserum, the rat VGF 342-350-NH2 peptide conjugated with bovine thyroglobulin via an additional D-tyrosine was used for guinea pig immunizations.…”

“…Immunohistochemistry was carried out as previously described (Cocco et al, 2010). Briefly, sections were incubated overnight with the VGF antisera diluted at 1:2000-4000 for the VGF C-terminus and 1:300-1000 for the others.…”