chromogranin peptides in brain diseases

BASIC NEUROSCIENCES, GENETICS AND IMMUNOLOGY - REVIEW ARTICLE

Chromogranin peptides in brain diseases

Michael Willis • Irmgard Leitner • Kurt A. Jellinger •

Josef Marksteiner

Received: 4 April 2011 / Accepted: 12 April 2011 / Published online: 30 April 2011

� Springer-Verlag 2011

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 exten-

sively. Data was collected from existing and new experi-

mental data and medline research. This review focuses on

synaptic changes elicited by chromogranin peptides immu-

noreactivity 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 chro-

mogranin A in neuroinflammation in Alzheimer’s disease

and ALS. Further understanding of role and function of

chromogranin peptides in neuropathological conditions is

still required.

Keywords Chromogranin A � Chromogranin B �Secretogranin II � Secretoneurin � Alzheimer’s disease

Abbreviations

Ab Amyloid-bAbPP Amyloid-b 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 3,30-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

Chromogranin peptides: biochemistry and in general

Chromogranins including chromogranin A (CgA), chro-

mogranin B (CgB) and secretogranin II (SgII) are soluble,

acidic glycophosphoproteins and are major constituents of

M. Willis

Department of General Psychiatry, Medical University

Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria

M. Willis � I. Leitner

Division of Molecular and Cellular Pharmacology,

Medical University Innsbruck, Peter Mayr Strasse 1,

6020 Innsbruck, Austria

K. A. Jellinger

Institute of Clinical Neurobiology, Kenyongasse 18,

1070 Vienna, Austria

J. Marksteiner (&)

Department of Psychiatry and Psychotherapy,

LKH Hall, Milserstrasse 10, 6060 Hall, Austria

e-mail: [email protected]

123

J Neural Transm (2011) 118:727–735

DOI 10.1007/s00702-011-0648-z

secretory large dense core-vesicles (LDCV) (Winkler and

Fischer-Colbrie 1992). In LDCV, they constitute the main

protein component of the intravesicular matrix (Taupenot

et al. 2003). Chromogranins (Cgs) are characterized by

numerous pairs of basic amino acids as potential sites for

intra- and extragranular processing (Helle 2010a). Chromo-

granins are prohormones that are transformed through

proteolytic processing in bioactive peptides, for example,

CgA-derived peptides like catestatin, vasostatin and SgII-

derived peptides like secretoneurin (Taupenot et al. 2003).

The presence of Cgs-derived active peptides has been linked

to the regulation of arterial blood pressure (Mahapatra et al.

2005). In response to adequate stimuli, granins are co-released

with neurotransmitters and hormones and appear in the cir-

culation as potential modulators of homeostatic processes

(Helle 2010b). The plasma level of the CgA peptide catestatin

is diminished in individuals with established hypertension and

those with a genetic risk of this disease (Salem et al. 2008).

Several functions have been proposed for Cgs including

Ca2? and catecholamine sequestration (Yoo and Jeon

2000), sorting of secretory proteins into the regulated

pathway (Huttner and Natori 1995; Obermuller et al.

2010), and as a source of bioactive peptides (Taupenot

et al. 2003; Helle 2004).

Chromogranin A is an endogenous inhibitor of nicotinic

cholinergic transmission (Mahata et al. 2004), promotes the

biogenesis of secretory granules and is involved in trans-

mitter accumulation and in the control of neurosecretion

(Montesinos et al. 2008). The intracellular functions of

CgB are binding with Ca2? and the modulation of inositol-

1,4,5-trisphosphate (IP3)-mediated Ca2? release (Thrower

et al. 2003; Helle 2004), biogenesis of secretory granules

and the sorting of secretory proteins to the regulated

secretory pathway (Obermuller et al. 2010). SgII-derived

peptide secretoneurin (SN) was found to have functions

similar to those of glial cell-derived neurotrophic factor,

which has a potent trophic effect on motor neurons (Acsadi

et al. 2002). Secretoneurin stimulates postnatal vasculo-

genesis by mobilization, migration, and incorporation of

endothelial progenitor cells (Kirchmair et al. 2004), as well

SN stimulates the release of dopamine from nigrostriatal

neurons (Saria et al. 1993).

Chromogranins are regulated by neuronal activity in

certain brain areas and by neurotrophic factors in neuronal

cell lines (Huang et al. 2001). In pathological brain con-

ditions, Cgs show distinct functions. CgA is likely to be a

mediator between neuronal, glial and inflammatory mech-

anisms found in Alzheimer disease (Heneka et al. 2010).

Secretoneurin acts directly on neurons after hypoxia and

ischemic insult to promote neuroprotection and neuronal

plasticity by activating the Jak2/Stat3 pathway (Shyu et al.

2008) and may contribute to neurogenic inflammation

(Helle 2010a).

Studies indicate a distinct localization for each of these

proteins in the human brain (Marksteiner et al. 1993, 1999).

CgA-LI in human brain was located preferentially to cortical

layers III and V, the mossy fibers of dentate granule cells, and

in pyramidal cells of area cornu ammois (CA2). Whereas

CgA-LI was found in pyramidal neurons, CgB-LI and SgII-

LI were largely co-contained in interneurons (Marksteiner

et al. 2002). For CgB-LI highest densities were observed in

the inner molecular layer of the dentate gyrus, for SgII-LI

highest densities were found in the innermost part of the

inner molecular layer throughout the hippocampal formation

(Kaufmann et al. 1998). CgB-LI and SgII-LI could be seen in

nerve cells throughout the dorsolateral, the orbitofrontal and

the entorhinal cortex, primary localized to layers II and III

(Lechner et al. 2004). No immunoreactivity for CgA, neither

for CgB and SgII, could be detected in glial cells.

Chromogranin peptides in AD

Alzheimer’s disease (AD) is morphologically characterized

by the presence of neurofibrillary tangles and amyloid-bplaques (Jellinger and Bancher 1998) together with a

degeneration of neurons and synapses (Arendt 2009). The

exact pathogenesis leading from these morphological

changes to progressive impairment in memory and cogni-

tion is not well understood yet. Correlations of synaptic

markers with cognition of the elderly suggest that cyto-

skeletal alterations are important in AD. Synaptophysin is

an intrinsic protein of the synaptic vesicle membrane and is

found in all types of synapses. It is proposed to play an

important role in synaptic vesicle priming, fusion of vesi-

cles and exocytosis. Loss of synapses led to the proposal

that synaptic loss is the structural basis of cognitive decline

in AD (Terry 2000). Accordingly, most studies focusing on

synaptic failure used synaptophysin as a marker for pre-

synaptic structures and correlated density of this peptide to

cognitive dysfunction (Arendt 2009). The use of chro-

mogranin peptides as markers of presynaptic structures,

offers additional insight in synaptic failure. Like synapto-

physin is an appropriate marker for small synaptic vesicles

(SSV), chromogranin peptides are useful markers for

LDCV (Torrealba and Carrasco 2004). Chromogranin

peptides are reported to be altered in the brains of Alz-

heimer patients. Not only plaque associated alterations of

chromogranin peptides were reported in AD, but as well

changes of density in specific brain regions.

Chromogranin A in Alzheimer’s disease

Chromogranin A was the first chromogranin found to be

present in neuritic plaques (Munoz 1991; Lassmann et al.

728 M. Willis et al.

123

1992; Yasuhara et al. 1994). It has been stated that CgA-

like immunoreactive neurites are major constituents of

senile plaques in Alzheimer patients (Munoz 1991), up to

20% of amyloid-b plaques contain CgA (Marksteiner et al.

2002). For CgA elevated levels were found in temporal

cortex of AD patients by immunoblots (Weiler et al. 1990)

and semiquantitative immunohistochemistry (Lassmann

et al. 1992). Contrary to these results a small reduction of

chromogranin A-like immunoreactivity (CgA-LI) was

found in the entorhinal cortex by immunohistochemistry

(Lechner et al. 2004). In the same studies, 40% of CgA-

positive plaques were surrounded and pervaded by

microglia, and CgA was reported to be found in glial

fibrillary acidic protein (GFAP)-positive astrocytes (Lech-

ner et al. 2004) (Fig. 1a, d). CgA-LI in GFAP-positive cells

could not be detected in transgenic (tg) mice carrying the

London (V717I) and Swedish (K670M/N671L) mutation

over-expressing human amyloid precursor protein APP751

(Fig. 2f) with an antibody directed against catestatin A327-

337. Since in human post-mortem brain of AD patients

CgA-LI was detected in GFAP-positive cells using the

monoclonal antibody LK2H10 (Lechner et al. 2004), dif-

ferences in antigen binding could be the reason for these

discrepancies. Immunohistochemistry performed in tg mice

showed a good agreement in the staining pattern for

polyclonal antibodies raised against the amino acid

sequences A327-337, A17-38 and CgA itself. Contrasting

these findings, an antibody raised against the peptide

catestatin of human CgA (A352-372) brought out a dif-

ferent staining pattern (not shown), comparable to findings

with a antibody against GE-19 of rat CgA in gerbils (Marti

et al. 2001).

In wild type mice, CgA-LI was found in cortical layers

III–V, in the perirhinal cortex as well in neurons of layer II.

In the hippocampal formation, intense CgA-LI was found

in the polymorphic layer and the mossy fiber system, strong

CgA-LI was found in pyramidal neurons of area cornu

ammonis 2, whereas areas CA1 and CA3 exhibited only

dispersed immunoreactivity. Already at the age of six

months amyloid-b plaques were CgA immunopositive in tg

mice. At month 12, a significant increase in the number of

immunopositive amyloid-b plaques was observed for CgA

throughout cortical areas and the hippocampus (Fig. 2a).

This increase was due a general higher number of amyloid-

b plaques at the age of 12 months. In cortical areas of

12 month-old-tg mice, we observed 6 ± 4 (mean/standard

deviation) CgA-immunopositive plaques per mm2, which

was clearly lower than that for CgB (Willis et al. 2008).

CgA-LI of plaques was characterized by huge swollen

centripedal buds, mainly reflecting dystrophic neurites

(Fig. 2d). An increase of varicosities, in part connecting

amyloid plaques, was observed for CgA.

Fig. 1 Immunhistological findings for Chromogranin A, Secretogr-

anin II and Chromogranin B in human AD brain. CgA-LI of amyloid-

b plaques in cortical layers (a), accompanied by CgA-Ll-positive

astrocytes (d). In the hippocampal formation SgII-LI (b) and CgB-LI

(c) was detected in amyloid-b plaques. Adjacent sections show SgII-

LI (e) and CgB-LI (f) in amyloid-b plaques. v vessel. Scale bar100 lm (a), 200 lm (b, c), 40 lm (d), 80 lm (e, f)

Chromogranin peptides in brain diseases 729

123

Chromogranin B in Alzheimer’s disease

In AD brain, CgB-LI-positive plaques were observed

mainly in the entorhinal cortex, as well in the subiculum,

the CA1 sector and the molecular layer of the dentate gyrus

(Fig. 1c). In total up to 25% of the amyloid-b-positive

plaques showed a co-labeling with CgB. A significant

reduction in density of CgB-LI was seen in the inner and

outer part of the inner molecular layer of the dentate gyrus,

the subiculum and the layers I, III and V of the entorhinal

cortex, the dorsolateral and orbitofrontal cortex (Markste-

iner et al. 2002; Lechner et al. 2004).

In transgenic mice over expressing human amyloid-bprotein precursor AbPP751 with the London (V717I) and

Swedish (K670M/N671L) mutations, CgB-immunoposi-

tive plaques could be detected at the age of 6 months, with

a significant increase of CgB-immunopositive plaques

throughout cortical areas and the hippocampus at the age of

12 months (Fig. 2b, e). About 60% of Ab-positive plaques

were CgB-immunoreactive. No significant differences in

CgB-LI density could be seen for any region between wild-

type and transgenic mice (Willis et al. 2008).

Secretogranin II in Alzheimer’s disease

In the first studies of SgII-LI in human AD brain, no SgII-

LI could be detected in amyloid-b plaques, as proposed due

to a higher processing by endogenous protease compared to

CgA (Lassmann et al. 1992). Further studies showed SgII-

LI in 40–60% of amyloid-b plaques, with highest levels in

the entorhinal cortex, followed in decreasing frequency by

the subiculum, the CA1 sector and the molecular layer of

the dentate gyrus (Kaufmann et al. 1998) (Fig. 1b). For

SgII, a co-localization with CgA and CgB was observed in

40–60% (Marksteiner et al. 2002).

A significant loss of SgII-LI could be detected in AD

brain in temporal cortex (Lassmann et al. 1992) and in the

innermost part of the inner molecular layer of the dentate

gyrus, the subiculum and the layers I, III and V of the

entorhinal cortex (Kaufmann et al. 1998; Marksteiner et al.

2002; Lechner et al. 2004).

In hAbPP-transgenic mice, SgII-immunoreactive pla-

ques were preferentially found in the deeper layers of the

cortex (Fig. 2c). In the hippocampal formation, plaques

were found numerously in stratum oriens, stratum radiatum

and inner molecular layer. As for the other Cgs, no sig-

nificant decrease in density of SgII-LI could be detected

(Willis et al. 2008).

Alterations of chromogranin peptides in AD

and implications

The high amount of CgA in dense core vesicles in dys-

trophic neurites around amyloid-b plaques indicate that

Fig. 2 Distribution of Chromogranin A (a), Chromogranin B (b) and

Secretogranin II (c) in hAbPP tg mice. Adjacent sections of CgA-LI

(d) and CgB-LI (e) showed co-localization. CgA-LI (green) could not

be detected in GFAP-positive cells (red) (f). Scale bar 200 lm

(a, b, c), 60 lm (d, e), 40 lm (f)


123

these cellular processes are of axonal origin and that neu-

rosecretory granules could be involved in the process of

amyloid b-formation.

As there is evidence that axon terminals from pyramidal

cortical neurons lack LDCV (Torrealba and Carrasco

2004), chromogranins are likely to be located in LDCV of

interneurons and therefore chromogranin immunoreactive

swollen neuritic endings surrounding Ab plaques seem to

originate from interneurons. Dystrophic neurites of senile

plaques show a selective accumulation of synaptic proteins

since several proteins that control exocytosis and neuro-

transmission were not contained in neuritic plaques in AD

patients (Dickson et al. 1999; Lechner et al. 2004).

In frontotemporal dementia, tau-positive Pick bodies

expressed CgB and SgII strongly, but CgA only weakly

(Bergmann et al. 1996). In transgenic mice carrying the

London (V717I) and Swedish (K670M/N671L) mutation

over-expressing human amyloid-b precursor protein

APP751 Chromogranin-LI could be detected in amyloid-bplaques (Willis et al. 2008) (Fig. 2). The accumulation of

chromogranin peptides in plaques did not depend on the

number of neurofibrillary tangles, as in this animal model

only a few tau-immunoreactive neuropil threads and no

neurofibrillary tangles were detected (Rockenstein et al.

2001). A co-localization of Cgs (usually intracellular) with

amyloid-b (usually extracellular) in swollen dystrophic

neurites could be a hint that intracellular amyloid-b is not

taken back from the plaque by the cell, but is part of the

secretory pathway, supporting the idea that intracellular

amyloid-b is at the beginning of the Ab cascade.

Chromogranin peptides and inflammation

Beneath amyloid-b, CgA was postulated as a potent pro-

inflammatory agent/inducer of neuroinflammation in AD

(Heneka et al. 2010). Receptor-mediated activation for

advanced glycation end products can serve as a potent

inducer of all three members of the chromogranin family

suggesting that these receptors might function as a regu-

lator of neuronal/neuroendocrine secretory phenotype

(Huttunen et al. 2002). Ligation of receptor for advanced

glycation end products by accumulating Ab fibrils might

up-regulate CgA expression, the secretion of which induces

a reactive and neurotoxic transformation of microglia,

resulting in apoptosis of microglia and neurons and there-

fore sustained inflammation in the AD brain, which has not

been shown so far for CgB or SN (Davenport et al. 2010).

CgA was found in GFAP-positive cells in postmortem

brain of AD, 40% of CgA-positive plaques were sur-

rounded by microglia. In contrast to CgA, CgB and SN

were not expressed in reactive astrocytes in human post-

mortem brain (Lechner et al. 2004). In transgenic mice for

hAPP, no CgA-LI could be detected in GFAP-positive

cells, regarding to methodological differences.

Chromogranin A is a potent activator of microglia and

activates microglial stress pathways (Ulrich et al. 2002;

Hooper et al. 2009). There is evidence for intracellular sig-

naling cascades elicited in microglia by CgA acting via

scavenger receptors (SR), which are upregulated in microglia

around senile plaques in AD tissue (Honda et al. 1998), to

induce ERK phosphorylation and expression of iNOS,

mitochondrial stress, release of glutamate and soluble neu-

rotoxins and ultimately microglial apoptosis and neuronal

death (Ulrich et al. 2002; Hooper and Pocock 2007). Fur-

thermore, amyloid-b peptides act as SR ligands (Alarcon

et al. 2005). Thus processes which modulate the interaction of

CgA with SR may have therapeutic potential in neurode-

generative diseases where microglial activation is implicated.

Chromogranin peptides in cerebral fluid

of Alzheimer’s disease patients

An analysis of cerebrospinal fluid (CSF) from patients with

multiple sclerosis, essential tremor, Alzheimer and Par-

kinson disease, did not reveal any differences in proteolytic

processing of Cgs when compared to control CSF, indi-

cating that in the four diseases investigated there is no

change in the proteolytic processing of the Cgs within the

LDCVs (Eder et al. 1998). The absolute levels of Cgs

varied in CSF collected in different hospitals; however,

their relative ratios were remarkable constant (Eder et al.

1998). In a recent paper, CgA in CSF was used together

with 11 proteins to identify biomarkers for early AD

pathology, to classify disease stage and to monitor patho-

logical progression. CgA together with NrCAM, YKL-40

and carnosinase improved the diagnostic accuracy of Ab42

and tau (Perrin et al. 2011).

In another CSF study, CgB and SgII were used as

markers for the secretory pathway. Since AbPP is produced

in the regulated secretory pathway of neurons, CSF levels

of the protease Beta-Secretase 1 (BACE1), which pro-

cesses AbPP into Ab, were measured in relation to

Cg-levels. CSF Cg-levels correlated to soluble amyloid-bprecursor protein (sbPP) and Ab peptides in AD, multiple

sclerosis, and controls, and to CSF BACE1. These results

suggest that a large part of AbPP in the human central

nervous system is processed in the regulated secretory

pathway of neurons (Mattsson et al. 2010).

Chromogranin peptides in schizophrenia

There is converging evidence that schizophrenia is char-

acterized by impairments of the synaptic machinery within


123

cerebral cortical circuits (Sweet et al. 2010). Several

studies have shown that proteins concentrated in presyn-

aptic terminals are significantly reduced in schizophrenia

(Selemon and Goldman-Rakic 1999; Eastwood and Harri-

son 2001). A reduction in synaptophysin peptide levels and

transcript levels was found in the schizophrenic hippo-

campus (Eastwood et al. 2000).

There is also evidence that chromogranins are altered in

the brains of schizophrenic patients (Iwazaki et al. 2004).

We have demonstrated an area specific reduction of CgB,

which is paralleled by a decrease of synapsin I (Nowa-

kowski et al. 2002). The loss of presynaptic proteins

involved in distinct steps of exocytosis may cause complex

synaptic disturbances in specific hippocampal subregions

resulting in imbalanced neurotransmitter availability in

schizophrenic patients. A reduction of CgA and CgB, but

not SgII, has been reported in the CSF in subjects with

schizophrenia (Landen et al. 1999), in sera of first onset

schizophrenia patients circulating levels of CgA were

increased (Guest et al. 2010). Single-marker and haplotype

analyses of single nucleotide polymorphisms (SNPs)

within the CHGA gene revealed a significant association

with schizophrenia with one SNP marker and with a two

marker haplotype (Takahashi et al. 2006). In an initial

genome-wide association study, it has been found that CgB

might be a candidate gene involved in the development of

schizophrenia (Kitao et al. 2000). In another Chinese study,

it was found that at least one locus in or close to the CHGB

gene confers risk for schizophrenia (Wu et al. 2007).

Phencyclidine (PCP) is a non-competitive NMDA glu-

tamate 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. We applied PCP to organo-

typic prefrontal cortex (PFC) slices, which caused a

decreased tissue and culture medium secretoneurin content

28 h after application. Sg II mRNA expression was

decreased after 28 h PCP application in cortical neurons

but not after 5 days of daily PCP administration. Thus, PCP

modulates Sg II expression in PFC tissue in the absence of

afferent inputs. The nature of these changes is dependent

upon the duration of exposure to and/or withdrawal from

PCP (Hinterhoelzl et al. 2003). A single dose of PCP

(10 mg/kg) led to a transient decrease in SN tissue levels in

the prefrontal cortex after 4 h followed by an increase in

SN tissue levels after 12 h. Repeated phencyclidine treat-

ment (10 mg/kg/day) for 5 days resulted in elevated SN

levels in cortical areas whereas CgA and CgB tissue levels

were unchanged. After the same treatment, a significant

increase in the number of SN containing neurons was

found in cortical layers II–III, and V–VI as revealed by

immunocytochemistry. The increases in SN levels were

paralleled by an increased number of SgII messenger RNA

containing neurons as well as by an increased expression of

SgII by individual neurons (Marksteiner et al. 2001).

Chromogranin peptides in amyotrophic

lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neu-

rodegenerative disease characterized by loss of motor

neurons in the motor cortex, brainstem and spinal cord,

accompanied by inflammation including microglial infil-

tration. As mentioned before, CgA is a potent activator of

Microglia (Kingham et al. 1999; Ciesielski-Treska et al.

2001), additionally a CHGB gene sequence variation has

been described as a risk factor and modulator of disease

onset in sporadic and familial ALS (Gros-Louis et al. 2009).

Superoxide dismutase 1 (SOD1) mutations are found in

20% of patients with ALS and cause motor neuron degen-

eration. The discovery of mutations in the human SOD1

gene encoding Cu, Zn superoxide dismutase in patients with

familial ALS has lead to the development of etiological

models of the disease. Expression of mutant SOD1 genes in

tg mice causes a progressive paralytic disease whose gen-

eral features resemble ALS in humans (Gurney 1997).

Chromogranins have been reported to interact with mutant

forms of superoxide dismutase that are linked to ALS, but

not with wild-type SOD1 in tg mice harboring the G39A

mutant of human SOD1 (Urushitani et al. 2006). In human

postmortem tissue Cgs were partially co-localized with

SOD1 in motor neurons (Schrott-Fischer et al. 2009). The

staining intensity for chromogranin peptides and synapto-

physin was significantly lower in the ventral horn of ALS

patients due to a loss in immunoreactive motor neurons,

varicose fibres and varicosities. For all chromogranins, the

remaining motor neurons displayed a characteristic staining

pattern consisting of an intracellular accumulation of

immunoreactivity with a high staining intensity. Confocal

microscopy of motor neurons revealed that superoxide

dismutase 1-immunopositive intracellular aggregates also

contained CgA, CgB and SgII. These findings indicate that

there is a loss of small and LDCV in presynaptic terminals.

The intracellular co-occurrence of superoxide dismutase 1

and chromogranins may suggest a functional interaction

between these proteins (Schrott-Fischer et al. 2009). Indeed

neuronal overexpression of CgA accelerated disease onset

in a SOD1 tg mouse model of ALS (Ezzi et al. 2010).

Conclusion

Chromogranin peptides are altered in a wide spectrum of

psychiatric and neurological disorders like Alzheimer’s


123

disease, ALS, multiple sclerosis, Lewy body disease, and

schizophrenia. Possible therapeutic use of chromogranin

peptides in neuroinflammation needs further investigation

of pathological mechanism. The use of chromogranins as

biomarkers for disease diagnosis might be of great poten-

tial clinical interest (Bartolomucci et al. 2010).

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