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Emmelie A Jansson,
Liyue Huang,
Ronny Malkey,
Mirco Govoni,
Carina Nihlén, Annika Olsson,
Margareta Stensdotter,
Joel Petersson,
Lena Holm,
Eddie Weitzberg,
Jon O Lundberg
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ABSTRACT: Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
Nature Chemical Biology 08/2008; 4(7):411-7. · 14.69 Impact Factor
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ABSTRACT: Enterovirus infections, in particular those with Coxsackieviruses, have been linked to the development of type 1 diabetes (T1D). Although animal models have demonstrated that interferons (IFNs) regulate virus-induced T1D by acting directly on the beta cell, little is known on the human pancreatic islet response to IFNs. Here we show that human islet cells respond to IFNs by expressing signature genes of antiviral defense. We also demonstrate that they express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which induce type I IFN production in infected cells. Finally, we show for the first time that the IFN-induced antiviral state provides human islets with a powerful protection from the replication of Coxsackievirus. This may be critical for beta cell survival and protection from virus-induced T1D in humans.
Virology 11/2007; 367(1):92-101. · 3.35 Impact Factor
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ABSTRACT: Enterovirus infections of the pancreatic islets are believed to trigger or precipitate the near total destruction of beta-cells that constitutes type 1 diabetes (T1D). This study investigated the ability of an anti-picornaviral compound, pleconaril, to block the replication of two beta-cell tropic Coxsackie B4 virus (CBV-4) strains in isolated human islets. The two strains, VD2921 and V89 4557, with demonstrated abilities to cause non-lytic persistence or lytic infection, respectively, in islets, represented two different potential mechanisms behind virus-induced T1D. The virus replication in the islets was studied with and without addition of pleconaril. In addition, islet morphology was studied every day. To test the effects of pleconaril and/or DMSO on the beta-cells' insulin secretion, glucose perifusions were performed on treated and untreated islets. Virus titrations showed a clear reduction of the replication of both strains after pleconaril treatment. The VD2921 strain was inhibited to undetectable levels. The V89 4557 strain, however, showed an initial reduction of titers but virus titers then increased despite the addition of a second dose of pleconaril. This incomplete inhibition of viral replication suggested the existence of a resistant subtype within this strain. Pleconaril treatment reduced the beta-cells' insulin secretion in response to glucose stimulation in some experiments and induced slight morphological changes to the islets compared to untreated controls. In summary, pleconaril reduced the replication of the two beta-cell tropic CBV-4 strains in human islets. However, genetic differences between these strains influenced the effectiveness of pleconaril treatment. This stresses the importance of using multiple viral strains in antiviral tests.
Antiviral Research 05/2007; 74(1):65-71. · 4.30 Impact Factor
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ABSTRACT: Enterovirus (EV) infections have been associated with the pathogenesis of type 1 diabetes (T1D). They may cause beta-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Evidence for EV involvement have been presented in several studies, EV-IgM antibodies have been reported in T1D patients, EV-RNA has been found in the blood from T1D patients at onset, and EV have been isolated from newly diagnosed T1D. Our aim was to study infections with EV isolates from newly diagnosed T1D patients in human pancreatic islets in vitro. Two of them (T1 and T2) originated from a mother and her son diagnosed with T1D on the same day, the other two (A and E) were isolated from a pair of twins at the time of diagnosis of T1D in one of them. Isolated human pancreatic islets were infected and viral replication, viability and degree of cytolysis as well as insulin release in response to high glucose were measured. All four EV isolates replicated in the islet cells and virus particles and virus-induced vesicles were seen in the cytoplasm of the beta-cells. The isolates varied in their ability to induce cytolysis and to cause destruction of the islets and infection with two of the isolates (T1 and A) caused more pronounced destruction of the islets. Infection with the isolate from the healthy twin boy (E) was the least cytolytic. The ability to secrete insulin in response to high glucose was reduced in all infected islets as early as 3 days post infection, before any difference in viability was observed. To conclude, strains of EV isolated from T1D patients at clinical presentation of T1D revealed beta-cell tropism, and clearly affected the function of the beta-cell. In addition, the infection caused a clear increase in the number of dead cells.
Virus Research 04/2007; 124(1-2):193-203. · 2.94 Impact Factor
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ABSTRACT: We show that genital infection with neurotropic HSV type 2 (HSV-2) induced a significant increase of the neuropeptide substance P (SP) within the genital tract of mice. SP was shown to weakly interfere with the HSV-2 replication. Furthermore, lack of SP signaling through the use of mice deficient in the SP receptor, neurokinin 1 receptor (NK1R), revealed an important role for SP in the innate defense against HSV-2. NK1R-deficient mice had significantly enhanced levels of HSV-2 in the genital tract and in the CNS following infection and a significantly accelerated disease progression, which was associated with an impaired NK cell activity locally in the vagina. Lack of NK1R signaling did, however, not impair the animals' ability to mount a protective immune response to HSV-2 following vaccination with an attenuated virus. Both NK1R+/+ and NK1R-/- mice developed strong HSV-2-specific Th1 T cell responses following vaccination. No genital viral replication was observed in either vaccinated NK1R-deficient or NK1R+/+ control animals following a genital HSV-2 challenge, and all of these animals survived without any symptoms of disease. In conclusion, the present results indicate that SP and NK1R signaling contributes to the innate resistance against HSV-2 infection in mice.
The Journal of Immunology 12/2005; 175(10):6802-11. · 5.79 Impact Factor
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ABSTRACT: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different beta-amyloid(42) (Abeta42) peptides can add further information to the combined use of tau and Abeta1-42 for predicting risk of progression of MCI to AD.
We used xMAP technology to simultaneously quantify different Abeta42 peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau181P) in CSF. Abeta42 peptide concentrations were measured by use of immunoreactivity toward Abeta monoclonal antibodies [3D6 (Abeta42-3D6), WO2 (Abeta42-WO2), 6E10 (Abeta42-6E10), and 4G8 (Abeta42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis.
The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) were significantly higher when we used Abeta42-3D6/Abeta42-WO2, Abeta42-3D6/Abeta42-6E10, or Abeta42-3D6/Abeta42-4G8 compared with Abeta42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length Abeta1-42 (Abeta42-3D6) compared with Abeta42-WO2, Abeta42-6E10, or Abeta42-4G8. Several Abeta42 peptides truncated at the amino terminus (Abeta11-42 and Abeta8-42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology.
The CSF markers tau, Abeta42 forms, and P-tau181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.
Clinical Chemistry 10/2005; 51(9):1650-60. · 7.91 Impact Factor
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ABSTRACT: The event that triggers the autoimmune destruction of insulin-producing beta-cells in type 1 diabetes mellitus (T1DM) is still unknown. Enterovirus, especially Coxsackievirus, infections have long been associated with this disease. Cytokines and chemokines induced by an enterovirus infection may act to trigger the autoimmune reactions that produce T1DM. Gene expression was examined in isolated human islets infected with a Coxsackievirus-B4 (CBV-4) strain causing lytic infection (V89-4557) and in islets infected with a CBV-4 strain establishing persistent infection (VD2921). Microarray analysis indicated that infection with the CBV-4 strains resulted in specific induction of a number of inflammatory genes, including IL-1beta, IL-6, IL-8, MCP-1, and RANTES. Importantly, the inflammatory genes induced by the CBV-4 infections differed in the two strains, with more cytokines being induced by the non-lytic CBV-4 strain than by the lytic strain. These cytokines and chemokines have the potential to rapidly induce inflammatory reactions when expressed in vivo and could contribute to the autoimmune reactions associated with the development of T1DM.
Biochemical and Biophysical Research Communications 06/2005; 330(2):571-6. · 2.48 Impact Factor
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ABSTRACT: We have investigated to what extent microinjected beta-endorphin could migrate from the rat brain parenchyma into the CSF compartment. Exogenous rat beta-endorphin (0.1 nmol) was microinjected into the left striatum 1 mm from the lateral ventricle in anesthetized male rats. CSF samples were collected at different time points up to 2 h post-injection from a catheter affixed to the atlanto-occipital membrane of the cisterna magna. Radioimmunoassay and mass spectrometry were performed on the CSF samples, and brain sections were immunostained for beta-endorphin and mu-opioid receptors. The beta-endorphin injected rats showed a marked increase in beta-endorphin immunoreactive (IR) material in the CSF, with a peak at 30-45 min post-injection, and this beta-endorphin-IR material existed mainly as the intact beta-endorphin peptide. The immunohistochemistry results revealed the appearance of distinct beta-endorphin-IR cell bodies in the globus pallidus and the bed nucleus of stria terminalis supracapsular part, regions distant from the injection site, at 2 h post-injection of exogenous beta-endorphin. The beta-endorphin-IR in several of the globus pallidus cell bodies colocalized with the mu-opioid receptor-IR at the cell surface. These findings show that upon delivery of synthetic beta-endorphin, there is a significant intracerebral spread of the injected peptide, reaching regions far from the site of injection via diffusion in the extracellular space and flow in the cerebrospinal fluid. This may be of relevance when interpreting studies based on intracerebral injections of peptides, and advances our knowledge regarding the migration of compounds within the brain.
Brain Research 05/2005; 1041(2):167-80. · 2.73 Impact Factor
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ABSTRACT: To simultaneously study several biomarkers for Alzheimer disease (AD), we used the xMAP technology to develop and evaluate a multiparametric bead-based assay for quantification of beta-amyloid((1-42)) [Abeta((1-42))], total tau (T-TAU), and hyperphosphorylated tau [P-TAU((181P))] in cerebrospinal fluid (CSF).
We compared the new multianalyte assay format with established ELISA techniques for the same proteins. We then performed a clinical study using CSF samples from patients with AD or mild cognitive impairment with progression to AD, healthy controls, and patients with other neurologic disorders.
The INNO-BIA AlzBio3 selectively and specifically measured Abeta((1-42)), T-TAU, and P-TAU((181P)) in the CSF. The new assay format had intra- and interassay CVs <10% for all analytes, even at low concentrations. The measurement range of the new assay was 3 to 4 logs compared with 1 to 2 logs for ELISAs. By plotting the mean of the values obtained in ELISA and the xMAP technology against the difference, we found that a correction factor could be used to convert xMAP results to ELISA values. The clinical study demonstrated that the new multiparametric assay could accurately distinguish patients with AD from patients with other neurologic disorders or control patients, with the diagnostic accuracy reaching recommended consensus criteria for specificity and sensitivity.
The new multiparametric method may be able to replace the corresponding ELISA methods.
Clinical Chemistry 02/2005; 51(2):336-45. · 7.91 Impact Factor
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ABSTRACT: Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer's disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated beta-amyloid (Abeta), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Abeta (Abeta1-42) and two soluble forms of APP (alpha-sAPP and ss-sAPP) in ventricular cerebrospinal fluid (VCSF) and Abeta(1-42) in plasma from 28 patients in a serial samples 0-11 days after TBI. The levels of alpha-sAPP, ss-sAPP and Abeta(1-42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Abeta(1-42) up to 1173 % from day 0-1 to day 5-6 and in VCSF-beta-sAPP up to 2033 % increase from day 0-1 to day 7-11. There was also a slight but significant increase of VCSF-beta-sAPP from day 0-1 to day 5-6 and day 7-11. By contrast, the plasma- Abeta(1-42) level is unchanged after injury. The marked increase in VCSFAbeta(1-42) implies that increased Abeta expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Abeta(1-42) in contrast to the marked increase in VCSF-Abeta(1-42) after severe TBI, supports the suggestion that plasma Abeta(1-42) does not reflect Abeta metabolism in the central nervous system (CNS).
Journal of Neurology 08/2004; 251(7):870-6. · 3.47 Impact Factor
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ABSTRACT: Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimers disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated -amyloid (A), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of A (A(1–42)) and two soluble forms of APP (-sAPP and sAPP) in ventricular cerebrospinal fluid (VCSF) and A(1–42) in plasma from 28 patients in a serial samples 0–11 days after TBI. The levels of -sAPP, -sAPP and A(1–42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-A(1–42) up to 1173 % from day 0–1 to day 5–6 and in VCSF--sAPP up to 2033 % increase from day 0–1 to day 7–11. There was also a slight but significant increase of VCSF--sAPP from day 0–1 to day 5–6 and day 7–11. By contrast, the plasma- A(1–42) level is unchanged after injury. The marked increase in VCSFA( 1–42) implies that increased A expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-A(1–42) in contrast to the marked increase in VCSF-A(1–42) after severe TBI, supports the suggestion that plasma A(1–42) does not reflect A metabolism in the central nervous system (CNS).
Journal of Neurology 06/2004; 251(7):870-876. · 3.47 Impact Factor
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Lisa Moberg, Annika Olsson,
Christian Berne,
Marie Felldin,
Aksel Foss,
Ragnar Källen,
Kaija Salmela,
Annika Tibell,
Gunnar Tufveson,
Bo Nilsson,
Olle Korsgren
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ABSTRACT: Islet-produced tissue factor (TF) triggers an adverse clotting reaction, the instant blood-mediated inflammatory reaction (IBMIR), providing a likely explanation for the need of tissue from multiple donors in clinical islet transplantation. In this study, the authors investigated whether compounds previously shown to affect TF and macrophage chemoattractant protein (MCP)-1 expression in monocytes and endothelial cells have the same effect in human islet cells.
Islets were cultured in the presence of l-arginine, cyclosporine A, enalapril, or nicotinamide for 48 hr, after which the TF content and MCP-1 expression were assessed. The effect of nicotinamide on IBMIR was evaluated by exposing the treated islets to fresh human ABO-compatible blood in an in vitro loop model.
Nicotinamide was the only compound that significantly reduced both TF and MCP-1. This reduction was dose-dependent. The level of MCP-1 was strongly correlated with TF expression (r2=0.98). In addition, the level of TF was also correlated with the ability of the islets to initiate IBMIR (r2=0.94).
TF and MCP-1 expression in human islets can be decreased by adding nicotinamide to the culture medium. These observations indicate that the adverse effects of IBMIR in clinical islet transplantation could be reduced without endangering the recipient using antithrombotic drugs.
Transplantation 12/2003; 76(9):1285-8. · 4.00 Impact Factor
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ABSTRACT: IL-1 beta has been proposed to be an important mediator linking infection, apnea, and sudden infant death syndrome. We hypothesized that IL-1 beta acts in this capacity by depressing brainstem respiratory neurons via a prostaglandin-dependent pathway. For studying the effects of IL-1 beta on respiration as well as the mechanism underlying its actions, 7-d-old rats received an initial injection (i.p.) of NaCl or a cyclooxygenase inhibitor (indomethacin, 10 mg/kg) followed by a second injection (i.p.) at 30 min of NaCl, recombinant rat IL-1 beta (10 microg/kg), or lipopolysaccharide (LPS; 100 microg/kg). Respiration during normoxia and in response to anoxia (100% N2) was examined at 60 min after the second injection using flow and barometric plethysmography. Animals given IL-1 beta breathed more slowly and died more often after anoxia. LPS also reduced the rats' ability to autoresuscitate and survive an anoxic challenge. Indomethacin prevented the depressive effects during normoxia and the adverse effects on survival. For investigating drug-induced changes in central respiratory activity, IL- 1 beta (1.0 or 1.25 ng/mL) and prostaglandin E2 (5 or 20 microg/L) was applied to the brainstem-spinal cord preparation of 0- to 4-d-old rats. Whereas IL-1 beta exerted no effect on respiration measured at the C4 ventral root during a 60-min period, prostaglandin E2 reversibly inhibited respiratory activity. These findings suggest that IL-1 beta does not inhibit respiratory neurons directly but may depress breathing and hypoxic defense via a prostaglandin-mediated mechanism.
Pediatric Research 10/2003; 54(3):326-31. · 2.70 Impact Factor
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Annika Olsson,
Kina Höglund,
Magnus Sjögren,
Niels Andreasen,
Lennart Minthon,
Lars Lannfelt,
Katharina Buerger,
Hans Jürgen Möller,
Harald Hampel,
Pia Davidsson,
Kaj Blennow
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ABSTRACT: One of the major histopathological hallmarks of Alzheimer's disease (AD) is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP (sAPP) and Abeta. We examined the cerebrospinal fluid (CSF) for alpha- and beta-secretase cleaved sAPP (alpha-sAPP and beta-sAPP) in 81 sporadic AD patients, 19 patients with mild cognitive impairment, and 42 healthy controls by using newly developed sandwich enzyme-linked immunosorbent assay methods. We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls. These findings further support the conclusion that there is no change in APP expression in sporadic AD. However, the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls. We also investigated the relationship between the CSF level of alpha/beta-sAPP and Abeta(42) and the apoE epsilon 4 (apoE4) allele. Significantly lower levels of CSF-alpha-sAPP were found in AD patients possessing one or two apoE4 alleles than in those not possessing the apoE4 allele. Neither the levels of CSF-beta-sAPP nor CSF-Abeta(42) differed when comparing ApoE4 allele-positive with allele-negative individuals.
Experimental Neurology 10/2003; 183(1):74-80. · 4.70 Impact Factor
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ABSTRACT: Expression of immune modulating mediators in human Islets of Langerhans could have important implications for development of autoimmunity in type 1 diabetes and influence the outcome of clinical islet transplantation. Islets obtained from five donors were analyzed at various times after isolation using cDNA array technology. The Atlas Human Cytokine/Receptor and Hematology/Immunology nylon membranes representing 268 genes and 406, respectively, were used and the relative expression of each gene analyzed. Of the 51 gene products identified, high mRNA expression of MCP-1, MIF, VEGF, and thymosin beta-10 was detected in all islet samples. IL-8, IL-1-beta, IL-5R, and INF-gamma antagonist were expressed in islets cultured for 2 days. IL-2R was expressed in islets cultured for more than 6 days. In conclusion, several inflammatory mediators were expressed in isolated islets, particularly at an early stage after isolation, indicating that a few days of culture could be beneficial for the outcome of islet transplantation.
Biochemical and Biophysical Research Communications 09/2003; 308(3):474-9. · 2.48 Impact Factor
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ABSTRACT: Rotational acceleration of the head, as occurs in falls, car crashes, and sport injuries, may result in diffuse brain damage, with acute and chronic neurological and psychiatric symptoms. The present study addresses the effects of rotational trauma on the neuronal cytoskeleton, which stabilizes perikaryal, dendritic and axonal shape and function. The study focuses upon the distribution of (1) the phosphorylated form of the heavy neurofilament subunit, (2) the light neurofilament subunit, and (3) beta-amyloid, a marker for brain injury. While normally restricted to axons, the phosphorylated heavy neurofilament subunits were drastically decreased in the axons after rotational trauma. Instead, they accumulated in the neuronal perikarya, normally devoid of the phosphorylated subunit. This alteration was seen, not only in the cerebral cortex, but also in the hippocampus, the cervical spinal cord, the cerebellum, the cranial nerves and the pyramidal tract. The distribution of the light subunit of neurofilaments was also altered post trauma. Only a weak beta-amyloid immunoreactivity was detected in the brains of control animals. Promptly after the trauma, a large number of beta-amyloid positive neurons appeared. Intensely co-localized immunoreactivity for the light subunit of neurofilaments and of beta-amyloid was seen 3 days after the rotational trauma axons of in the subcortical white matter and in the granule cell layer of the dentate gyrus as well as in neurons of the hypoglossal nucleus. The reported alterations in the central nervous system neurons are similar to those in the human brain after closed head injury and in chronic degenerative diseases. Regions of importance for social behavior, memory and body movement were affected.
Journal of Neurotrauma 03/2003; 20(2):169-78. · 3.65 Impact Factor
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ABSTRACT: Accumulation of beta-amyloid (Abeta) in the brain is one of the central lesions in Alzheimer's disease (AD). Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP, Abeta(40) and Abeta(42). Platelets have been regarded as the primary source of circulating APP and Abeta. Plasma levels of Abeta may therefore be dependent on platelet activation. We analysed Abeta(40/42) in plasma in the presence of physiological agonists of platelet activation such as adenosine diphosphate, collagen, thrombin, and a synthetic agonist, thrombin receptor activator peptide 6. We found that the levels of Abeta(40/42) in plasma were not related to platelet activation, suggesting that sampling techniques affecting platelet activation do not confound measurement of Abeta(40/42 )in plasma.
Dementia and Geriatric Cognitive Disorders 02/2003; 16(2):93-7. · 2.14 Impact Factor
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ABSTRACT: We investigated the clinical and biological effects of cholesterol-lowering treatment with a statin in 19 patients with Alzheimer's disease. They received simvastatin 20 mg/day for 12 weeks in an open trial. Primary efficacy parameters were the changes after 12 weeks in the cerebrospinal fluid (CSF) levels of beta-amyloid(42) (Abeta(42)), alpha-secretase-cleaved amyloid precursor protein (alpha-sAPP), beta-secretase-cleaved APP (beta-sAPP), tau, phospho-tau and the plasma levels of Abeta(42). A secondary efficacy parameter was the change in the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog) score. After 12 weeks, CSF alpha-sAPP and CSF beta-sAPP were significantly reduced (p < 0.001), but the CSF levels of tau, phospho-tau, Abeta(42) and the plasma levels of Abeta(42) were unchanged. The ADAS-cog score was slightly increased (p < 0.05). The results suggest that simvastatin acts directly on the processing of APP by inhibiting both the alpha- and the beta-secretase pathways.
Dementia and Geriatric Cognitive Disorders 01/2003; 16(1):25-30. · 2.14 Impact Factor
