Skip to main content

Advertisement

SpringerLink
Log in

Chromogranin peptides in brain diseases

  • Basic Neurosciences, Genetics and Immunology - Review article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Synaptic disturbances may play a key role in the pathophysiology of neuropsychiatric diseases. In this article, we review immunohistological findings of chromogranin peptides in neurodegenerative and neurodevelopmental disorders, with particular emphasis on Alzheimer’s disease, the disorder chromogranins have been studied most extensively. Data was collected from existing and new experimental data and medline research. This review focuses on synaptic changes elicited by chromogranin peptides immunoreactivity in Alzheimer’s disease, as well in schizophrenia and amyotrophic lateral sclerosis (ALS). An imbalanced availability of chromogranin peptides may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Since chromogranin A was postulated as a potent proinflammatory agent, we focused on chromogranin A in neuroinflammation in Alzheimer’s disease and ALS. Further understanding of role and function of chromogranin peptides in neuropathological conditions is still required.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

Aβ:

Amyloid-β

AβPP:

Amyloid-β precursor protein

ALS:

Amyotrophic lateral sclerosis

AD:

Alzheimer’s disease

BACE1:

Beta-secretase 1

CA:

Cornu ammonis

CgA:

Chromogranin A

CgB:

Chromogranin B

Cgs:

Chromogranins

CSF:

Cerebrospinal fluid

DAB:

3,3′-diaminobenzidine

GFAP:

Glial fibrillary acidic protein

IP3 :

Inositol-1,4,5-trisphosphate

LDCV:

Large dense core vesicles

-LI:

Like immunoreactivity

NMDA:

N-Methyl-d-aspartate

PFC:

Prefrontal cortex

PCP:

Phencyclidin

SgII:

Secretogranin II

SN:

Secretoneurin

SNPs:

Single nucleotide polymorphisms

SOD1:

Superoxide dismutase 1

SR:

Scavenger receptors

SSV:

Small synaptic vesicles

References

  • Acsadi G, Anguelov RA, Yang H, Toth G, Thomas R, Jani A, Wang Y, Ianakova E, Mohammad S, Lewis RA, Shy ME (2002) Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum Gene Ther 13:1047–1059

    Article  PubMed  CAS  Google Scholar 

  • Alarcon R, Fuenzalida C, Santibanez M, Von BR (2005) Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound beta-amyloid. J Biol Chem 280:30406–30415

    Article  PubMed  CAS  Google Scholar 

  • Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179

    Article  PubMed  Google Scholar 

  • Bartolomucci A, Pasinetti GM, Salton SR (2010) Granins as disease-biomarkers: translational potential for psychiatric and neurological disorders. Neuroscience 170:289–297

    Google Scholar 

  • Bergmann M, Kuchelmeister K, Schmid KW, Kretzschmar HA, Schroder R (1996) Different variants of frontotemporal dementia: a neuropathological and immunohistochemical study. Acta Neuropathol 92:170–179

    Article  PubMed  CAS  Google Scholar 

  • Ciesielski-Treska J, Ulrich G, Chasserot-Golaz S, Zwiller J, Revel MO, Aunis D, Bader MF (2001) Mechanisms underlying neuronal death induced by chromogranin A-activated microglia. J Biol Chem 276:13113–13120

    Article  PubMed  CAS  Google Scholar 

  • Davenport CM, Sevastou IG, Hooper C, Pocock JM (2010) Inhibiting p53 pathways in microglia attenuates microglial-evoked neurotoxicity following exposure to Alzheimer peptides. J Neurochem 112:552–563

    Article  PubMed  CAS  Google Scholar 

  • Dickson TC, King CE, McCormack GH, Vickers JC (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Exp Neurol 156:100–110

    Article  PubMed  CAS  Google Scholar 

  • Eastwood SL, Harrison PJ (2001) Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res Bull 55:569–578

    Article  PubMed  CAS  Google Scholar 

  • Eastwood SL, Cairns NJ, Harrison PJ (2000) Synaptophysin gene expression in schizophrenia. Investigation of synaptic pathology in the cerebral cortex. Br J Psychiatry 176:236–242

    Article  PubMed  CAS  Google Scholar 

  • Eder U, Leitner B, Kirchmair R, Pohl P, Jobst KA, Smith AD, Mally J, Benzer A, Riederer P, Reichmann H, Saria A, Winkler H (1998) Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases. J Neural Transm 105:39–51

    Article  PubMed  CAS  Google Scholar 

  • Ezzi SA, Lariviere R, Urushitani M, Julien JP (2010) Neuronal over-expression of chromogranin A accelerates disease onset in a mouse model of ALS. J Neurochem 115:1102–1111

    Article  PubMed  Google Scholar 

  • Gros-Louis F, Andersen PM, Dupre N, Urushitani M, Dion P, Souchon F, D’Amour M, Camu W, Meininger V, Bouchard JP, Rouleau GA, Julien JP (2009) Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 106:21777–21782

    Article  PubMed  CAS  Google Scholar 

  • Guest PC, Wang L, Harris LW, Burling K, Levin Y, Ernst A, Wayland MT, Umrania Y, Herberth M, Koethe D, van Beveren JM, Rothermundt M, McAllister G, Leweke FM, Steiner J, Bahn S (2010) Increased levels of circulating insulin-related peptides in first-onset, antipsychotic naive schizophrenia patients. Mol Psychiatry 15:118–119

    Article  PubMed  CAS  Google Scholar 

  • Gurney ME (1997) The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. J Neurol Sci 152(Suppl 1):S67–S73

    Article  PubMed  CAS  Google Scholar 

  • Helle KB (2004) The granin family of uniquely acidic proteins of the diffuse neuroendocrine system: comparative and functional aspects. Biol Rev Camb Philos Soc 79:769–794

    Article  PubMed  Google Scholar 

  • Helle KB (2010a) Regulatory peptides from chromogranin A and secretogranin II: putative modulators of cells and tissues involved in inflammatory conditions. Regul Pept 165:45–51

    Article  PubMed  CAS  Google Scholar 

  • Helle KB (2010b) The chromogranin A-derived peptides vasostatin-I and catestatin as regulatory peptides for cardiovascular functions. Cardiovasc Res 85:9–16

    Article  PubMed  CAS  Google Scholar 

  • Heneka MT, O’Banion MK, Terwel D, Kummer MP (2010) Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm 117:919–947

    Article  PubMed  CAS  Google Scholar 

  • Hinterhoelzl JK, Salimi K, Humpel C, Singewald N, Adlassnig C, Fischer-Colbrie R, Fleischhacker WW, Marksteiner J (2003) Differential effects of phencyclidine application on secretogranin II expression in organotypic slices of rat prefrontal cortex. J Neurochem 87:13–21

    Article  PubMed  CAS  Google Scholar 

  • Honda M, Akiyama H, Yamada Y, Kondo H, Kawabe Y, Takeya M, Takahashi K, Suzuki H, Doi T, Sakamoto A, Ookawara S, Mato M, Gough PJ, Greaves DR, Gordon S, Kodama T, Matsushita M (1998) Immunohistochemical evidence for a macrophage scavenger receptor in Mato cells and reactive microglia of ischemia and Alzheimer’s disease. Biochem Biophys Res Commun 245:734–740

    Article  PubMed  CAS  Google Scholar 

  • Hooper C, Pocock JM (2007) Chromogranin A activates diverse pathways mediating inducible nitric oxide expression and apoptosis in primary microglia. Neurosci Lett 413:227–232

    Article  PubMed  CAS  Google Scholar 

  • Hooper C, Fry VA, Sevastou IG, Pocock JM (2009) Scavenger receptor control of chromogranin A-induced microglial stress and neurotoxic cascades. FEBS Lett 583:3461–3466

    Article  PubMed  CAS  Google Scholar 

  • Huang CM, Shui HA, Wu YT, Chu PW, Lin KG, Kao LS, Chen ST (2001) Proteomic analysis of proteins in PC12 cells before and after treatment with nerve growth factor: increased levels of a 43-kDa chromogranin B-derived fragment during neuronal differentiation. Brain Res Mol Brain Res 92:181–192

    Article  PubMed  CAS  Google Scholar 

  • Huttner WB, Natori S (1995) Regulated secretion. Helper proteins for neuroendocrine secretion. Curr Biol 5:242–245

    Article  PubMed  CAS  Google Scholar 

  • Huttunen HJ, Kuja-Panula J, Rauvala H (2002) Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J Biol Chem 277:38635–38646

    Article  PubMed  CAS  Google Scholar 

  • Iwazaki T, Shibata I, Niwa S, Matsumoto I (2004) Selective reduction of chromogranin A-like immunoreactivities in the prefrontal cortex of schizophrenic subjects: a postmortem study. Neurosci Lett 367:293–297

    Google Scholar 

  • Jellinger KA, Bancher C (1998) Neuropathology of Alzheimer’s disease: a critical update. J Neural Transm Suppl 54:77–95

    PubMed  CAS  Google Scholar 

  • Kaufmann WA, Barnas U, Humpel C, Nowakowski K, DeCol C, Gurka P, Ransmayr G, Hinterhuber H, Winkler H, Marksteiner J (1998) Synaptic loss reflected by secretoneurin-like immunoreactivity in the human hippocampus in Alzheimer’s disease. Eur J Neurosci 10:1084–1094

    Article  PubMed  CAS  Google Scholar 

  • Kingham PJ, Cuzner ML, Pocock JM (1999) Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation. J Neurochem 73:538–547

    Article  PubMed  CAS  Google Scholar 

  • Kirchmair R, Gander R, Egger M, Hanley A, Silver M, Ritsch A, Murayama T, Kaneider N, Sturm W, Kearny M, Fischer-Colbrie R, Kircher B, Gaenzer H, Wiedermann CJ, Ropper AH, Losordo DW, Patsch JR, Schratzberger P (2004) The neuropeptide secretoneurin acts as a direct angiogenic cytokine in vitro and in vivo. Circulation 109:777–783

    Article  PubMed  CAS  Google Scholar 

  • Kitao Y, Inada T, Arinami T, Hirotsu C, Aoki S, Iijima Y, Yamauchi T, Yagi G (2000) A contribution to genome-wide association studies: search for susceptibility loci for schizophrenia using DNA microsatellite markers on chromosomes 19, 20, 21 and 22. Psychiatr Genet 10:139–143

    Article  PubMed  CAS  Google Scholar 

  • Landen M, Grenfeldt B, Davidsson P, Stridsberg M, Regland B, Gottfries CG, Blennow K (1999) Reduction of chromogranin A and B but not C in the cerebrospinal fluid in subjects with schizophrenia. Eur Neuropsychopharmacol 9:311–315

    Article  PubMed  CAS  Google Scholar 

  • Lassmann H, Weiler R, Fischer P, Bancher C, Jellinger K, Floor E, Danielczyk W, Seitelberger F, Winkler H (1992) Synaptic pathology in Alzheimer’s disease: immunological data for markers of synaptic and large dense-core vesicles. Neuroscience 46:1–8

    Article  PubMed  CAS  Google Scholar 

  • Lechner T, Adlassnig C, Humpel C, Kaufmann WA, Maier H, Reinstadler-Kramer K, Hinterholzl J, Mahata SK, Jellinger KA, Marksteiner J (2004) Chromogranin peptides in Alzheimer’s disease. Exp Gerontol 39:101–113

    Article  PubMed  CAS  Google Scholar 

  • Mahapatra NR, O’Connor DT, Vaingankar SM, Hikim AP, Mahata M, Ray S, Staite E, Wu H, Gu Y, Dalton N, Kennedy BP, Ziegler MG, Ross J, Mahata SK (2005) Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 115:1942–1952

    Article  PubMed  CAS  Google Scholar 

  • Mahata SK, Mahata M, Wen G, Wong WB, Mahapatra NR, Hamilton BA, O’Connor DT (2004) The catecholamine release-inhibitory “catestatin” fragment of chromogranin a: naturally occurring human variants with different potencies for multiple chromaffin cell nicotinic cholinergic responses. Mol Pharmacol 66:1180–1191

    Article  PubMed  CAS  Google Scholar 

  • Marksteiner J, Saria A, Kirchmair R, Pycha R, Benesch H, Fischer-Colbrie R, Haring C, Maier H, Ransmayr G (1993) Distribution of secretoneurin-like immunoreactivity in comparison with substance P- and enkephalin-like immunoreactivities in various human forebrain regions. Eur J Neurosci 5:1573–1585

    Article  PubMed  CAS  Google Scholar 

  • Marksteiner J, Bauer R, Kaufmann WA, Weiss E, Barnas U, Maier H (1999) PE-11, a peptide derived from chromogranin B, in the human brain. Neuroscience 91:1155–1170

    Article  PubMed  CAS  Google Scholar 

  • Marksteiner J, Weiss U, Weis C, Laslop A, Fischer-Colbrie R, Humpel C, Feldon J, Fleischhacker WW (2001) Differential regulation of chromogranin A, chromogranin B and secretogranin II in rat brain by phencyclidine treatment. Neuroscience 104:325–333

    Article  PubMed  CAS  Google Scholar 

  • Marksteiner J, Kaufmann WA, Gurka P, Humpel C (2002) Synaptic proteins in Alzheimer’s disease. J Mol Neurosci 18:53–63

    Article  PubMed  CAS  Google Scholar 

  • Marti E, Ferrer I, Blasi J (2001) Differential regulation of chromogranin A, chromogranin B and secretoneurin protein expression after transient forebrain ischemia in the gerbil. Acta Neuropathol (Berl) 101:159–166

    CAS  Google Scholar 

  • Mattsson N, Johansson P, Hansson O, Wallin A, Johansson JO, Andreasson U, Andersen O, Haghighi S, Olsson M, Stridsberg M, Svensson J, Blennow K, Zetterberg H (2010) Converging pathways of chromogranin and amyloid metabolism in the brain. J Alzheimers Dis 20:1039–1049

    PubMed  CAS  Google Scholar 

  • Montesinos, Machado JD, Camacho M, Diaz J, Morales YG, Alvarez dlR, Carmona E, Castaneyra A, Viveros OH, O’Connor DT, Mahata SK, Borges R (2008) The crucial role of chromogranins in storage and exocytosis revealed using chromaffin cells from chromogranin A null mouse. J Neurosci 28:3350–3358

    Article  PubMed  CAS  Google Scholar 

  • Munoz DG (1991) Chromogranin A-like immunoreactive neurites are major constituents of senile plaques. Lab Invest 64:826–832

    PubMed  CAS  Google Scholar 

  • Nowakowski C, Kaufmann WA, Adlassnig C, Maier H, Salimi K, Jellinger KA, Marksteiner J (2002) Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. Schizophr Res 58:43–53

    Article  PubMed  Google Scholar 

  • Obermuller S, Calegari F, King A, Lindqvist A, Lundquist I, Salehi A, Francolini M, Rosa P, Rorsman P, Huttner WB, Barg S (2010) Defective secretion of islet hormones in chromogranin-B deficient mice. PLoS One 5:e8936

    Article  PubMed  Google Scholar 

  • Perrin RJ, Craig-Schapiro R, Malone JP, Shah AR, Gilmore P, Davis AE, Roe CM, Peskind ER, Li G, Galasko DR, Clark CM, Quinn JF, Kaye JA, Morris JC, Holtzman DM, Townsend RR, Fagan AM (2011) Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer’s disease. PLoS One 6:e16032

    Article  PubMed  CAS  Google Scholar 

  • Rockenstein E, Mallory M, Mante M, Sisk A, Masliaha E (2001) Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1–42). J Neurosci Res 66:573–582

    Article  PubMed  CAS  Google Scholar 

  • Salem RM, Cadman PE, Chen Y, Rao F, Wen G, Hamilton BA, Rana BK, Smith DW, Stridsberg M, Ward HJ, Mahata M, Mahata SK, Bowden DW, Hicks PJ, Freedman BI, Schork NJ, O’Connor DT (2008) Chromogranin A polymorphisms are associated with hypertensive renal disease. J Am Soc Nephrol 19:600–614

    Article  PubMed  CAS  Google Scholar 

  • Saria A, Troger J, Kirchmair R, Fischer-Colbrie R, Hogue-Angeletti R, Winkler H (1993) Secretoneurin releases dopamine from rat striatal slices: a biological effect of a peptide derived from secretogranin II (chromogranin C). Neuroscience 54:1–4

    Article  PubMed  CAS  Google Scholar 

  • Schrott-Fischer A, Bitsche M, Humpel C, Walcher C, Maier H, Jellinger K, Rabl W, Glueckert R, Marksteiner J (2009) Chromogranin peptides in amyotrophic lateral sclerosis. Regul Pept 152:13–21

    Article  PubMed  CAS  Google Scholar 

  • Selemon LD, Goldman-Rakic PS (1999) The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45:17–25

    Article  PubMed  CAS  Google Scholar 

  • Shyu WC, Lin SZ, Chiang MF, Chen DC, Su CY, Wang HJ, Liu RS, Tsai CH, Li H (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Invest 118:133–148

    Article  PubMed  CAS  Google Scholar 

  • Sweet RA, Fish KN, Lewis DA (2010) Mapping synaptic pathology within cerebral cortical circuits in subjects with schizophrenia. Front Hum Neurosci 4:44

    PubMed  Google Scholar 

  • Takahashi N, Ishihara R, Saito S, Maemo N, Aoyama N, Ji X, Miura H, Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y, Ozaki N, Inada T (2006) Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population. Schizophr Res 83:179–183

    Article  PubMed  Google Scholar 

  • Taupenot L, Harper KL, O’Connor DT (2003) The chromogranin-secretogranin family. N Engl J Med 348:1134–1149

    Article  PubMed  CAS  Google Scholar 

  • Terry RD (2000) Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol 59:1118–1119

    PubMed  CAS  Google Scholar 

  • Thrower EC, Choe CU, So SH, Jeon SH, Ehrlich BE, Yoo SH (2003) A functional interaction between chromogranin B and the inositol 1, 4, 5-trisphosphate receptor/Ca2+ channel. J Biol Chem 278:49699–49706

    Article  PubMed  CAS  Google Scholar 

  • Torrealba F, Carrasco MA (2004) A review on electron microscopy and neurotransmitter systems. Brain Res Brain Res Rev 47:5–17

    Article  PubMed  CAS  Google Scholar 

  • Ulrich G, Ciesielski-Treska J, Taupenot L, Bader MF (2002) Chromogranin A-activated microglial cells induce neuronal apoptosis. Ann N Y Acad Sci 971:560–562

    Article  PubMed  CAS  Google Scholar 

  • Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9:108–118

    Article  PubMed  CAS  Google Scholar 

  • Weiler R, Lassmann H, Fischer P, Jellinger K, Winkler H (1990) A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease. FEBS Lett 263:337–339

    Article  PubMed  CAS  Google Scholar 

  • Willis M, Prokesch M, Hutter-Paier B, Windisch M, Stridsberg M, Mahata SK, Kirchmair R, Wietzorrek G, Knaus HG, Jellinger K, Humpel C, Marksteiner J (2008) Chromogranin B and Secretogranin II in transgenic mice overexpressing human APP751 with the London (V717I) and Swedish (K670M/N671L) mutations and in Alzheimer patients. J Alzheimers Dis 13:123–135

    PubMed  CAS  Google Scholar 

  • Winkler H, Fischer-Colbrie R (1992) The chromogranins A and B: the first 25 years and future perspectives. Neuroscience 49:497–528

    Article  PubMed  CAS  Google Scholar 

  • Wu S, Ma J, Xing Q, Xu Y, Meng J, Cao D, Feng G, He L (2007) Further evidence that the chromogranin B gene confers predisposition to schizophrenia: a family-based association study in Chinese. J Neural Transm 114:641–644

    Article  PubMed  CAS  Google Scholar 

  • Yasuhara O, Kawamata T, Aimi Y, McGeer EG, McGeer PL (1994) Expression of chromogranin A in lesions in the central nervous system from patients with neurological diseases. Neurosci Lett 170:13–16

    Article  PubMed  CAS  Google Scholar 

  • Yoo SH, Jeon CJ (2000) Inositol 1, 4, 5-trisphosphate receptor/Ca2+ channel modulatory role of chromogranin A, a Ca2+ storage protein of secretory granules. J Biol Chem 275:15067–15073

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Psychiatry, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria

    Michael Willis

  2. Division of Molecular and Cellular Pharmacology, Medical University Innsbruck, Peter Mayr Strasse 1, 6020, Innsbruck, Austria

    Michael Willis & Irmgard Leitner

  3. Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria

    Kurt A. Jellinger

  4. Department of Psychiatry and Psychotherapy, LKH Hall, Milserstrasse 10, 6060, Hall, Austria

    Josef Marksteiner

Authors
  1. Michael Willis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irmgard Leitner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kurt A. Jellinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Josef Marksteiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Josef Marksteiner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Willis, M., Leitner, I., Jellinger, K.A. et al. Chromogranin peptides in brain diseases. J Neural Transm 118, 727–735 (2011). https://doi.org/10.1007/s00702-011-0648-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-011-0648-z

Keywords

Search

Navigation