The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease

Abstract

Abstract-A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. By size exclusion chromatography, the cleavage of prosomatostatin to somatostatin-14 is almost totally abolished in the cortex of PC2 null mice, while the proportions of prosomatostatin and somatostatin-28 are increased. By immunohistochemistry, PC1 and PC2 were localized in many neuronal elements in human frontal and temporal cortex. The convertases levels were quantified by Western blot, as well as the protein 7B2 which is required for the production of active PC2. No significant change in PC1 levels was observed in Alzheimer's disease. In contrast, a marked decrease in the ratio of the PC2 precursor to the total enzymatic pool was observed in the frontal cortex of Alzheimer patients. This decrease coincides with an increase in the binding protein 7B2. However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.

Reduced neuronal co-localisation of nardilysin and the putative α-secretases ADAM10 and ADAM17 in Alzheimer’s disease and Down syndrome brains

“…Less neuronal NRDc might, for example, affect neuropeptide levels in AD brains. In this way, NRDc might contribute to the dysregulation of dynorphins in AD (Yakovleva et al 2007) and, possibly, to the elevated levels of the isoform somatostatin-28 Winsky-Sommerer et al 2003), which appear in parallel to the well-documented general somatostatin deficit in AD (Rossor et al 1984;Beal et al 1987;Mouradian et al 1991;Dournaud et al 1995). Although there is only little, if any, overlap of NRDc and somatostatin-28 immunoreactive nerve cell bodies in human brain (Bernstein et al 2007), a reduced somatostatin-28 metabolising function of NRDc (Csuhai et al 1998) cannot be ruled out in AD.…”

An Early Reduction in GH Peak Amplitude in Preproghrelin-Deficient Male Mice Has a Minor Impact on Linear Growth

“…The lower limit of sensitivity was 12.5 pg/tube and the intra-and interassays of variation were of 3% and 4.9%, respectively. A SRIH RIA was performed as previously published (25). The sensitivity threshold of the assay was 0.5 pg/tube and the intra-and interassay coefficients of variation were below 10%.…”

Somatostatin: A Novel Substrate and a Modulator of Insulin-Degrading Enzyme Activity

“…34,35 Furthermore, it is well known that somatostatin performs crucial roles in the brain and that its decrease represents a pathological feature of AD, even though this reduction is not accompanied by an alteration of proteolytic processing of peptide precursors. 36 Although the mechanism that couples alterations of the somatostatinergic system to AD remains unclear, recently, it has been shown that somatostatin regulates β-amyloid metabolism through the modulation of neprilysin proteolytic activity. 19,23,24 In this work, we show for the first time that the neuropeptide somatostatin is not only a novel substrate of IDE but also a modulator of its activity toward a FβA peptide, corresponding to the 10-25 amino acid sequence of the Aβ(1-40), which displays a behavior quite similar to that observed for the intact Aβ(1-40) (see Fig.…”