Adipocytokines and CD34 progenitor cells in Alzheimer's disease.

Abstract

Alzheimer's disease (AD) and atherosclerosis share common vascular risk factors such as arterial hypertension and hypercholesterolemia. Adipocytokines and CD34(+) progenitor cells are associated with the progression and prognosis of atherosclerotic diseases. Their role in AD is not adequately elucidated.
In the present study, we measured in 41 patients with early AD and 37 age- and weight-matched healthy controls blood concentrations of adiponectin and leptin by enzyme linked immunoabsorbent assay and of CD34(+) progenitor cells using flow cytometry. We found significantly lower plasma levels of leptin in AD patients compared with the controls, whereas plasma levels of adiponectin did not show any significant differences (AD vs. control (mean ± SD): leptin:8.9 ± 5.6 ng/mL vs.16.3 ± 15.5 ng/mL;P = 0.038; adiponectin:18.5 ± 18.1 µg/mL vs.16.7 ± 8.9 µg/mL;P = 0.641). In contrast, circulating CD34(+) cells were significantly upregulated in AD patients (mean absolute cell count ± SD:253 ± 51 vs. 203 ± 37; P = 0.02) and showed an inverse correlation with plasma levels of leptin (r =  -0.248; P = 0.037). In logistic regression analysis, decreased leptin concentration (P = 0.021) and increased number of CD34(+) cells (P = 0.036) were both significantly associated with the presence of AD. According to multifactorial analysis of covariance, leptin serum levels were a significant independent predictor for the number of CD34(+) cells (P = 0.002).
Our findings suggest that low plasma levels of leptin and increased numbers of CD34(+) progenitor cells are both associated with AD. In addition, the results of our study provide first evidence that increased leptin plasma levels are associated with a reduced number of CD34(+) progenitor cells in AD patients. These findings point towards a combined involvement of leptin and CD34(+) progenitor cells in the pathogenesis of AD. Thus, plasma levels of leptin and circulating CD34(+) progenitor cells could represent an important molecular link between atherosclerotic diseases and AD. Further studies should clarify the pathophysiological role of both adipocytokines and progenitor cells in AD and possible diagnostic and therapeutic applications.

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Adipocytokines and CD34+Progenitor Cells in
Alzheimer’s Disease
Boris Bigalke1,2, Brigitte Schreitmu ¨ller3, Kateryna Sopova1, Angela Paul1, Elke Stransky3, Meinrad
Gawaz1, Konstantinos Stellos1*., Christoph Laske3*.
1Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universita ¨t Tu ¨bingen, Tu ¨bingen, Germany, 2Division of Imaging Sciences, School of
Medicine, King’s College London, The Rayne Institute, London, United Kingdom, 3Department of Psychiatry and Psychotherapy, University of Tu ¨bingen, Tu ¨bingen,
Germany
Abstract
Background: Alzheimer’s disease (AD) and atherosclerosis share common vascular risk factors such as arterial hypertension
and hypercholesterolemia. Adipocytokines and CD34+progenitor cells are associated with the progression and prognosis of
atherosclerotic diseases. Their role in AD is not adequately elucidated.
Methods and Findings: In the present study, we measured in 41 patients with early AD and 37 age- and weight-matched
healthy controls blood concentrations of adiponectin and leptin by enzyme linked immunoabsorbent assay and of CD34+
progenitor cells using flow cytometry. We found significantly lower plasma levels of leptin in AD patients compared with the
controls, whereas plasma levels of adiponectin did not show any significant differences (AD vs. control (mean6SD):
leptin:8.965.6 ng/mL vs.16.3615.5 ng/mL;P=0.038; adiponectin:18.5618.1 mg/mL vs.16.768.9 mg/mL;P=0.641). In con-
trast, circulating CD34+cells were significantly upregulated in AD patients (mean absolute cell count6SD:253651 vs.
203637; P=0.02) and showed an inverse correlation with plasma levels of leptin (r=20.248; P=0.037). In logistic
regression analysis, decreased leptin concentration (P=0.021) and increased number of CD34+cells (P=0.036) were both
significantly associated with the presence of AD. According to multifactorial analysis of covariance, leptin serum levels were
a significant independent predictor for the number of CD34+cells (P=0.002).
Conclusions: Our findings suggest that low plasma levels of leptin and increased numbers of CD34+progenitor cells are
both associated with AD. In addition, the results of our study provide first evidence that increased leptin plasma levels are
associated with a reduced number of CD34+progenitor cells in AD patients. These findings point towards a combined
involvement of leptin and CD34+progenitor cells in the pathogenesis of AD. Thus, plasma levels of leptin and circulating
CD34+progenitor cells could represent an important molecular link between atherosclerotic diseases and AD. Further
studies should clarify the pathophysiological role of both adipocytokines and progenitor cells in AD and possible diagnostic
and therapeutic applications.
Citation: Bigalke B, Schreitmu ¨ller B, Sopova K, Paul A, Stransky E, et al. (2011) Adipocytokines and CD34+Progenitor Cells in Alzheimer’s Disease. PLoS ONE 6(5):
e20286. doi:10.1371/journal.pone.0020286
Editor: Maria A. Deli, Biological Research Center of the Hungarian Academy of Sciences, Hungary
Received January 18, 2011; Accepted April 28, 2011; Published May 25, 2011
Copyright: ? 2011 Bigalke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was supported in part by Grants from the Fortu ¨ne Program of the University of Tu ¨bingen F1331299 to CL and 1795-1-0 to KS (Konstantinos
Stellos), from the grant of the German Cardiac Society (DGK) ‘molecular imaging of atheroslerotic plaques’ to BB, from Hirnliga e.V. to KS (Konstantinos Stellos)
and from the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG:Li849/3-1;SFB:SFB-TR19-B8N) Sonderforschungsbereich/Transregio-19
‘‘Inflammatory cardiomyopathy - Molecular pathogenesis and treatment’’ to KS (Konstantinos Stellos) and MG. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: christoph.laske@med.uni-tuebingen.de (CL); konstantinos.stellos@med.uni-tuebingen.de (KS)
. These authors contributed equally to this work.
Introduction
Increased plasma leptin levels have been found to be associated
with a lower risk of incident dementia and Alzheimer’s disease
(AD) [1]. Cerebrovascular dysfunction is a well-known finding in
patients with AD [2], and leptin may be an important therapeutic
target [3]. Even though plasma levels of adipocytokines leptin and
adiponectin are associated with the progression and prognosis of
atherosclerotic diseases showing a significant increase in patients
with acute coronary syndrome compared to patients with stable
angina pectoris [4], the assessment of adipocytokine plasma levels
in AD patients needs further elucidation due to contrasting results
of adipocytokine plasma concentrations [5].
AD and atherosclerosis share the same classical cerebro-/
cardiovascular risk factors such as hypertension, hyperlipidemia,
diabetes mellitus type 2, obesity and smoking [6]. Considering this
vascular component in AD allows us to find key aspects including
epidemiology, genetics, pathogenesis, diagnosis, and treatment in
an analogous view to coronary artery disease (CAD) [7].
Previously, our group has described associations of plasma levels
of platelet-derived soluble collagen receptor glycoprotein VI
(GPVI) as well as of stromal cell-derived factor 1 (SDF-1) with
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AD patients [8,9]. We have recently shown that CD34+progenitor
cells are stage-dependently upregulated in AD patients [10], which
may reflect vascular repair processes in the brain [11]. Several
studies examined assocations of adipocytokines and progenitor
cells and focused on their vascular effects in patients with acute
myocardial infarction and with metabolic syndrome [12–14]. To
date, no study has focused on the presence of AD and the potential
association between adipocytokines and number of CD34+
progenitor cells in AD patients so far. Even though AD
neurodegeneration, stroke, and CAD share similar vascular repair
mechanisms [15], differential levels and therapeutic effects of
progenitor cells in vascular regeneration produced inconsistent
results in cardiovascular research [16,17].
Regarding patients with CAD, differential plasma concentra-
tions of adiponectin have been controversially discussed for the
predictive value [4,18–20]. Moreover, adiponectin seems to act in
a protective way in comorbidities such as diabetes mellitus type 2,
insulin resistance, metabolic syndrome, and inflammation [21–
23], whereas correlations of leptin to classical risk markers such as
troponin-I and C-reactive protein may reflect the degree of
inflammation in the process of plaque instability [24].
The aim of this study was to differentially evaluate AD presence
and find associations between the plasma levels of both
adipocytokines (leptin and adiponectin) and their influence on
the number of CD34+progenitor cells reflecting the initiation of
vascular healing process in the brain in patients with AD.
Methods
Subjects
We consecutively evaluated 41 patients with early AD from our
Memory Clinic at the University Hospital of Psychiatry and
Psychotherapy Tuebingen and compared them to 37 healthy
elderly controls. Patients’ demographic and clinical details are
presented in Table 1.
Patients with AD fulfilled the criteria of ICD-10, DSM-IV and
the National Institute of Neurologic and Communicative Disor-
ders and Stroke and the Alzheimer’s Disease and Related
Disorders Association (NINCDS-ADRDA) for probable AD
[25]. The clinical severity of cognitive impairment was assessed
by the mini-mental state examination (MMSE) [26].
AD patients or control subjects with current or a history of
depression or psychosis, with major physical illness, alcohol or
substance abuse or use of psychoactive medications were excluded
from the study.
The study was performed according to the ethical principles of
the Declaration of Helsinki (sixth revision, 2008) and was
approved by the local ethics committee of the University Hospital
Tuebingen. We obtained written informed consent from all
subjects participating at the study (in case of AD patients: by
themselves or by legally authorized representatives).
Blood sampling
Blood samples were obtained in the morning (9.00–10.00 A.M.;
in the fasting state). Venous blood was filled into 5 mL
ethylenediaminetetraacetic acid (EDTA) plasma probes for the
determination of baseline concentrations of adiponectin, and
leptin using an enzyme-linked immunosorbent assay (ELISA) kit as
well as into 3.8% citrate plasma tubes for the peripheral blood
monocnuclear cell isolation.
Flow cytometry
According to previous protocols, mononuclear cells were
isolated using a Ficoll density gradient (Biocoll, Biochrom, Berlin,
Germany) [10,27]. Mononuclear cells were resuspended in 100 ml
of phosphate buffered saline. For flow cytometric analyis, we used
Fluorescein (FITC)-conjugated anti-CD34 antibodies (Becton
Dickinson, San Jose, USA; clone 8G12) and IgG1-FITC (BD
Biosciences Pharmingen, USA; clone MOPC-21) served as
negative isotype control. Each measurement was performed in
duplicate. After 250,000 events have been reached in a
lymphocyte gate, we used the absolute cell counts as units.
ELISA
Plasma levels of adiponectin and leptin were determined in a
total group of 78 consecutive AD patients and healthy controls
using a commercially available ELISA kit according to the
manufacturer’s guidelines (R&D Systems, Minneapolis, MN,
USA). EDTA plasma probes were centrifuged for 15 minutes at
10,000 g within 30 minutes of collection. Probes were aliquotted
and stored at 220uC before analysis. Lower detection limits of
these assays were 15.6 pg/mL for leptin and 0.079 ng/mL for
adiponectin. These assays recognize recombinant and natural
leptin and recombinant and natural (low, middle and high
molecular weight) human total adiponectin.
Data analysis
Data are presented as mean 6 standard deviation (SD). All tests
were two-tailed and statistical significance was considered for P
values less than 0.05. For corrections of multiple testing, a
Bonferroni–Holm correction was applied. A multiple logistic
Table 1. Patients’ Characteristics and Premedication on
Hospital Admission.
Characteristics
All
(n=78)
AD
(n=41)
Control
(n=37)
P Value
(AD vs.
Control)
Age – years 71610.2 74.369.167.3610.20.598
Sex – no. (%)0.415
Female40 (51.3)22 (53.7) 18 (48.6)
Male38 (48.7) 19 (46.3)19 (51.4)
Cerebro-/cardiovascular
risk factors – no. (%)
Arterial hypertension 33 (42.3)18 (43.9)15 (40.5)0.472
Hyperlipidaemia28 (35.9)15 (36.6)13 (35.1) 0.442
Diabetes mellitus6 (7.7)3 (7.3) 3 (8.1) 0.612
Family history of CAD9 (11.5)6 (14.6) 3 (8.1)0.295
Smoking10 (12.8)7 (17.1) 3 (8.1)0.201
Obesity (BMI$ $30)16 (20.5)6 (14.6)10 (35.4)0.271
Comorbidities
Coronary artery
disease (CAD)
12 (15.4)7 (17.1)5 (13.5)0.454
History of myocardial
Infarction/stroke
7 (8.9) 4 (23.1) 3 (8.1)0.558
Mini-mental state
examination score
(MMSE)
24.565.819.964.629.460.60.001
Premedication – no. (%)
ACE Inhibitors31 (39.7)17 (41.5) 14 (37.8) 0.463
Statins17 (21.8) 11 (26.8)6 (16.2)0.196
NSAID20 (25.6)13 (31.7) 7 (18.9) 0.151
*mean 6 standard deviation. AD denotes Alzheimer’s disease, CAD coronary
artery disease, BMI body mass index, ACE angiotensin converting enzyme,
NSAID non-steroidal anti-inflammatory drugs.
doi:10.1371/journal.pone.0020286.t001
Adipocytokines and CD34+Cells in AD
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regression analysis implementing an automatic stepwise selection
algorithm for risk factor inclusion was performed to assess
independent association of parameters with the presence of AD.
Adjustment by possible confounders was performed by the
multifactorial analysis of covariance for the decadic logarithm of
plasma levels of leptin and adiponectin and the number of CD34+
progenitor cells, respectively. The patients have been matched
according to age, sex, body weight, classical cerebro-/cardiovas-
cular risk factors, comorbidities, and medical treatment regarding
angiotensin converting enzyme (ACE) inhibitors, statins, and non-
steroidal anti-inflammatory drugs. Continuous variables were
tested for normal distribution with the Kolmogorov-Smirnov test.
The two-tailed t-test was used to assess differences between two
groups in case of normal distribution. The Mann-Whitney U-test
was used to assess differences between two groups in case of non-
normal distribution. Comparison of categorical variables was
generated by the Pearson chi-square test. Correlations were
assessed with the Spearman correlation coefficient test of the data.
All statistical analyses were performed using computer software
program SPSS version 15.0.1 for windows (SPSS Inc., Chicago,
IL, USA).
Results
We consecutively evaluated 41 patients with early AD (22
women, 19 men; mean age 6 SD: 74.369.1 years) and compared
them to 37 healthy elderly controls (18 women, 19 men; mean age
6 SD: 67.3610.2 years). AD patients showed a mean MMSE
score 6 SD of 19.864.5. The control group had a normal
cognitive status according to clinical examination and MMSE
score (mean MMSE score 6 SD: 29.460.6). Patients’ demo-
graphic and clinical details are presented in Table 1.
We found significantly lower plasma levels of leptin in AD
patients compared with healthy controls (Fig. 1A), whereas plasma
levelsof adiponectin did not show any significant differences (AD vs.
control (mean6SD): leptin: 8.965.6 ng/mL vs. 16.3615.5 ng/
mL; P=0.038; adiponectin: 18.5618.1 mg/mL vs. 16.768.9 mg/
mL; P=0.641) (Fig. 1B). However, plasma levels of both
adipocytokines significantly correlated with each other (r=0.402;
P=0.001)inthe combinedsamplepoolofADpatientsandcontrols.
The number of circulating CD34+progenitor cells were
significantly upregulated in AD patients (mean absolute cell
count6SD: 253651 vs. 203637; P=0.02) (Fig. 1C). Moreover,
Figure 1. Plasma levels of adipocytokines leptin and adiponectin, and number of CD34+progenitor cells in Alzheimer’s disease
(AD). (A) AD patients showed significantly lower plasma leptin levels compared with healthy controls (P=0.038). (B) Plasma levels of adiponectin did
not show any significant differences between AD patients and healthy controls (P=0.641). (C) Number of CD34+progenitor cells [mean absolute cell
count] was significantly upregulated in patients with AD compared to control (P=0.02). (D) Plasma levels of leptin inversely correlated with the
number of CD34+progenitor cells (r=20.248; P=0.037).
doi:10.1371/journal.pone.0020286.g001
Adipocytokines and CD34+Cells in AD
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we found a significant, inverse correlation with the plasma levels of
leptin (r=20.248; P=0.037) (Fig. 1D).
To test whether plasma levels of adipocytokines (leptin,
adiponectin) and CD34+progenitor cells are independently
associated with the presence of AD, we performed a multivariate
logisticregression analysisincludingparameterssuch asage,gender,
classical cerebro-/cardiovascular risk factors, comorbidities, and
medication. Among the variables tested, plasma levels of leptin were
negatively (P=0.021) and number of CD34+progenitor cells
positively (P=0.036) associated with the presence of AD (Table 2).
Comparisons of the decadic logarithm of plasma levels of leptin,
adiponectin and CD34+cells between AD and controls were
adjusted by possible confounders such as age, sex, body weight,
classical cerebro-/cardiovascular risk factors, comorbidities, and
medical treatment. Thus, plasma levels of leptin and CD34+cells
have been independently associated with AD compared to controls
(leptin: P=0.002; CD34+cells: P=0.022), whereas adiponectin
plasma levels neither have been associated with AD (P=0.470) nor
have been influenced by any other potential confounders
(all,P.0.05) (Table 3).
Plasma levels of leptin significantly correlated with the severity of
AD according to MMSE score (r=0.264; P=0.019) (Fig. 2A),
whereas increased plasma levels of adiponectin showed an inverse
trend to a lower MMSE score, although this did not reach a
statistically significant level (r=20.137; P=0.062). Moreover, high
leptin plasma levels positively correlated with an increased body
mass index (BMI) (r=0.428; P=0.001) (Fig. 2B), and inversely
correlated with advancing age (r=20.225; P=0.048) (Fig. 2C).
However, high adiponectin levels did not correlate with BMI
(r=0.119; P=0.314) or with age, respectively (r=0.099; P=0.396).
Discussion
The major findings of the present observational study are: 1)
AD patients had significantly decreased plasma levels of leptin
compared with healthy controls, whereas circulating CD34+cells
were significantly upregulated in AD patients; 2) in logistic
regression analysis, decreased leptin concentration and increased
number of CD34+cells were both significantly associated with the
presence of AD; 3) high plasma levels of leptin inversely correlated
with a lower MMSE score and an advancing age and positively
correlated with an increase in BMI.
Adipocytokines leptin and adiponectin are associated with the
incidence, progression and outcome of atherosclerotic diseases,
although previous studies have provided contrasting results about
differential plasma concentrations of the adipocytokines in CAD,
ischemic stroke and AD [4,5,18–20,28,29]. Recently, circulating
leptin has been described to be associated with reduced incidence of
dementia and AD and with a higher total cerebral brain volume
determined by magnetic resonance imaging in asymptomatic older
adults [1]. These results suggesting a protective role of leptin were
supported by our findings with decreased baseline plasma levels of
leptin in AD patients compared to healthy controls. Furthermore, a
decrease of circulating leptin may also have a detrimental effect on
the severity of cognitive dysfunction as determined by MMSE score.
To the best of our knowledge, the potential association between
adipocytokines and the number of progenitor cells has not been
reported so far in AD patients. Several in vivo experiments have
shown that leptin may significantly increase the recruitment of
hematopoetic as well as endothelial progenitor cells and promote
vascular regeneration after vascular injury [30–32]. As an
angiogenic factor, leptin induces neovascularization as well as
vascular permeability [33,34]. Moreover, leptin may regulate
hippocampal progenitor cells enhancing neurogenesis in adult
Table 2. Multivariate Logistic Regression Modeling.
Parameters Tested
Regression
Coefficient b
P Value
Leptin
20.2070.021
Adiponectin
CD34+Cells
20.0390.108
0.1150.036
Age
20.3350.142
Gender (Male)
20.1960.347
Arterial hypertension
20.0480.543
Hyperlipidemia0.1330.072
Diabetes mellitus 0.231 0.081
Family history of CAD 0.0620.369
Smoking0.1090.171
Body mass index0.3220.207
Coronary artery disease (CAD)0.0080.558
History of myocardial
infarction/stroke
0.1210.484
ACE Inhibitors
20.0130.255
Statins 0.2850.093
NSAID 0.0240.243
doi:10.1371/journal.pone.0020286.t002
Table 3. Multifactorial Analysis of Covariance.
CategoryFactor
P Value
Leptin
P Value
Adipo-
nectin
P
Value
CD34+
Cells
Age
Years0.289 0.6540.273
Sex
Male vs. Female0.445 0.1890.108
Cerebro-/
cardiovascular
risk factors
Arterial hypertension0.6120.2230.435
Hyperlipidemia0.9050.418 0.503
Diabetes mellitus 0.9640.5620.700
Family history of CAD0.5560.701 0.932
Smoking 0.6980.577 0.629
Body mass index 0.2790.1760.194
Comorbidities
Coronary artery
disease (CAD)
0.8340.3140.341
History of myocardial
infarction/stroke
0.6560.1650.560
Medication
ACE Inhibitors0.4670.8340.319
Statins0.9480.9230.666
NSAID0.6550.5710.205
Groups
AD vs. Control 0.0020.4700.022
doi:10.1371/journal.pone.0020286.t003
Adipocytokines and CD34+Cells in AD
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mice [35]. In AD patients, we have recently reported increased
number of circulating CD34+/CD133+progenitor cells in patients
with moderate to severe dementia [10]. In the present study, we
could demonstrate an inverse correlation between decreased
plasma leptin levels and increased circulating CD34+progenitor
cells. This finding is in line with the results of a recent study in
patients with obesity and could be due to a negative feedback
mechanism of pro-angiogenic factors [13].
Although plasma levels of adiponectin have been frequently
examined in previous studies for CAD and ischemic stroke [4,15–
17,26],nonehasfocused onpatientswith ADsofar.Thus,wefound
that adiponectin has neither been associated with AD nor has been
influenced by any other possible confounders. However, plasma
levels of adiponectin are inversely correlated to MMSE scores,
although this did not reach a statistically significant level. Of
interest,plasmalevelsofboth adipocytokinessignificantlycorrelated
with each other, which has been described before in patients with
CAD [4]. It is well-known that pathological changes in the brain
and cognitive dysfunction are associated with an age-related decline
[36]. In addition, age is known as the major risk factor of AD [36].
Interestingly, we found a significant inverse correlation between
leptin plasma levels and age in the whole study population of AD
patients and healthy controls. This result indicates that leptin
plasma levels decrease with advancing age, possibly in a continuum
that culminates with AD. Furthermore, weight loss often precedes
dementia in AD patients [37] and BMI, hyperlipidemia, and
diabetes mellitus have a significant impact on the expression of
leptin and adiponectin [37,38]. However, associations of leptin and
BMI or MMSE score produced inconsistent results, which, in some
cases, may be explained with leptin resistance in obese humans [39–
41]. Our collective showed that high leptin plasma levels positively
correlated with an increased BMI.
Previous studies have revealed how leptin may be directly
associated with AD pathology in the brain [1,6,42]. Two major
hallmarks of the molecular pathogenesis of AD are accumulation
of amyloid-beta (Ab) peptides to amyloid plaques and deposition of
hyperphosphorylated tau proteins to neurofibrillary tangles [6].
Recent experimental studies with animal models of AD have
shown that cholesterol-enriched diets and cholesterol metabolites
increase Ab and phosphorylated tau levels in the brain by reducing
Figure 2. Correlation of baseline concentrations of leptin according to mini-mental state examination (MMSE) score. (A) Lower
plasma levels of leptin significantly correlated with a lower MMSE score (r=0.264; P=0.019). (B) High leptin plasma levels positively correlated with an
increased body mass index (BMI) (r=0.428; P=0.001) and (C) inversely correlated with advancing age (r=20.225; P=0.048).
doi:10.1371/journal.pone.0020286.g002
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leptin levels [42]. Thus, treatment with leptin reversed the 27-
OHC-induced increase in Ab and phosphorylated tau by
decreasing the levels of b-secretase (BACE-1) and glycogen
synthetase kinase-3b (GSK-3b) respectively [42]. The protective
effect of leptin administration against AD pathology in the brain
has also been demonstrated in other experimental studies [43].
These experimental findings indicate that leptin administration
could be a promising new treatment strategy against AD.
Furthermore, adipocytokines may contribute as a diagnostic tool
to a multimarker strategy in AD simultaneously evaluating
biomarkers such as endothelin-1, atrial natriureticpeptide, and
adrenomedullin with immune modulating, metabolic, and vascular
characteristics [44]. The development and assessment of a multi-
marker panel of platelet activity, vascular repair and tissue
regeneration could be worthwhile, as we have previously found
associations of plasma levels of platelet-derived soluble GPVI, SDF-
1, and CD34+/CD133+progenitor cells with AD patients [8–10].
In conclusion, our findings suggest that low plasmalevels of leptin
and increased numbers of CD34+progenitor cells are both
associated with AD. In addition, the results of our study provide
first evidence that increased leptin plasma levels are associated with
a reduced number of CD34+progenitor cells in AD patients. These
findings point towards a combined involvement of leptin und
CD34+progenitor cells in the pathogenesis of AD. Thus, plasma
levels of leptin and circulating CD34+progenitor cells could
represent an important molecular link between atherosclerotic
diseases and AD. Further studies should clarify the pathophysio-
logical role and interaction of both adipocytokines and progenitor
cells in AD and possible diagnostic and therapeutic applications.
Acknowledgments
We thank Antonia Kolmar for technical assistance.
Author Contributions
Conceived and designed the experiments: BB K. Stellos CL. Performed the
experiments: ES AP. Analyzed the data: BB BS K. Stellos CL.
Contributed reagents/materials/analysis tools: K. Sopova MG CL.
Wrote the paper BB.:
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