Catestatin--a novel neuropeptide in carcinoid tumors of the appendix.

BACKGROUND: The aim of the study was to investigate the immunohistochemical distribution of the novel neuropeptide catestatin in carcinoid tumors. Catestatin, a novel 21 amino acid neuropeptide derived from chromogranin A, was determined immunohistochemically in 30 carcinoid tumors of the appendix and various carcinoid tumors of other localities. MATERIALS AND METHODS: Paraffin-embedded tissues from 30 carcinoid tumors of the appendix and 16 other carcinoid tumors (5 bronchus-, 5 stomach-, 2 small bowel-, 4 large bowel carcinoid tumors) were incubated with antibodies specific for catestatin, chromogranin A and chromogranin B. Immunohistochemical staining of catestatin was compared to staining with chromogranin A and B. Western blot analysis was performed in one patient with ileal carcinoid. RESULTS: Thirty patients (20 women, 10 men) with carcinoid tumors of the appendix and 16 patients with other localized carcinoid tumors were investigated. Twenty-six of the appendiceal tumors were localized in the apex of the appendix and 4 tumors in the midportion; none of the tumors was localized at the base of the appendix. Median tumor diameter was 10.7 mm (range 4-18 mm). Immunoreactivity to catesatatin was positive in 28 patients (negative in 2, 0-10% in 11 patients, 11-50% in 14 patients, 51-100% in 3 patients). In 16 patients with carcinoid tumors in various other localizations, catestatin was also expressed. Western blot analysis of ileal carcinoid showed abundant catestatin reactivity with accelerated processing of chromogranin A in the tumor tissue. CONCLUSION: Catestatin derived from chromogranin A, which is the most widely distributed marker of neuroendocrine tumors, is expressed in high frequency in carcinoid tumors of the appendix (93.3%).

Chromogranin peptides in Alzheimer's disease.

Synaptic disturbances may play a key role in the pathophysiology of Alzheimer's disease. To characterize differential synaptic alterations in the brains of Alzheimer patients, chromogranin A, chromogranin B and secretoneurin were applied as soluble constituents for large dense core vesicles, synaptophysin as a vesicle membrane marker and calbindin as a cytosolic protein. In controls, chromogranin B and secretogranin are largely co-contained in interneurons, whereas chromogranin A is mostly found in pyramidal neurons. In Alzheimer's disease, about 30% of beta-amyloid plaques co-labelled with chromogranin A, 20% with secretoneurin and 15% with chromogranin B. Less than 5% of beta-amyloid plaques contained synaptophysin or calbindin, respectively. Semiquantitative immunohistochemistry revealed a significant loss for chromogranin B- and secretoneurin-like immunoreactivity in the dorsolateral, the entorhinal, and orbitofrontal cortex. Chromogranin A displayed more complex changes. It was the only chromogranin peptide to be expressed in glial fibrillary acidic protein containing cells. About 40% of chromogranin A immunopositive plaques and extracellular deposits were surrounded and pervaded by activated microglia. The present study demonstrates a loss of presynaptic proteins involved in distinct steps of exocytosis. An imbalanced availability of chromogranins may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Chromogranin A is likely to be a mediator between neuronal, glial and inflammatory mechanisms found in Alzheimer disease.

Differential effects of phencyclidine application on secretogranin II expression in organotypic slices of rat prefrontal cortex.

Phencyclidine (PCP) is a non-competitive NMDA glutamate receptor antagonist that induces psychotomimetic effects in humans and experimental animals. Chronic PCP exposure elicits signs of persistently altered frontal brain activity and related behaviors which are also seen in patients with schizophrenia. Secretogranin II (sg II) belongs to the chromogranin family of proteins that exist in large dense core vesicles in nervous tissue. In the brain, 90% of sg II is processed to the small peptide secretoneurin. We previously detected differential effects of single-dose and subchronic PCP administration on sg II expression in the rat prefrontal cortex (PFC). In the present study, we applied PCP to organotypic PFC slices. PCP application for 28 h induced decreased tissue and culture medium secretoneurin content. In contrast, incubation with the adenylate cyclase activator forskolin caused significantly increased secretoneurin levels after 8 h. PCP for 4 h followed by 24 h without PCP resulted in increased culture medium secretoneurin content but no change in tissue levels. sg II mRNA expression was decreased after 28 h PCP application in cortical neurons. Immunohistochemical and TUNEL staining profiles indicated that the alterations were not due to neurodegeneration. PCP for 5 days changed neither the secretoneurin tissue or culture medium levels, nor the sg II mRNA expression. These results demonstrate that PCP modulates sg II expression in PFC tissue in the absence of afferent inputs and that the nature of these changes is dependent upon the duration of exposure to and/or withdrawal from PCP.

Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia.

Synaptic disturbances may play a key role in the pathophysiology of schizophrenia. This study was designed to further investigate possible synaptic alterations in the brains of chronic schizophrenic patients. Chromogranin B was applied as a marker for large dense core vesicles and synapsin I as a protein associated with the synaptic vesicle membrane. The distribution and density of chromogranin B-and synapsin I-like immunoreactivity in subregions of the hippocampus was compared between controls (n = 16) and patients with schizophrenia (n = 17). The overall distribution of hippocampal chromogranin B- and synapsin I-like immunoreactivity was similar in controls and in schizophrenic patients with the highest densities in the terminal field of mossy fibers and in the inner molecular layer of the dentate gyrus. In schizophrenic hippocampi, a significant reduction in the density of chromogranin B-like immunoreactivity was found in the CA4 and CA3 but not in the CA1 area of the dentate gyrus based on computerized image analysis. The loss of immunoreactivity was localized to mossy fibers and terminals surrounding hilar interneurons. Double-labelling immunohistochemistry revealed that synapsin I was co-expressed with chromogranin B in these neuronal structures and was also significantly reduced in schizophrenic hippocampi. The present study demonstrates an area-specific reduction of chromogranin B which is paralleled by a decrease of synapsin I. The loss of presynaptic proteins involved in distinct steps of exocytosis may cause complex synaptic disturbances in specific hippocampal subregions resulting in an imbalanced neurotransmitter availability in schizophrenic patients.