Lähettäjä: Soijuv Lähetetty: 2.1.2006 11:20
Sveitsiläinen tutkimus: Borreliabakteereita löytyi alzheimerin tautia sairastavien henkilöiden aivokudoksesta:
J Alzheimers Dis. 2004 Dec;6(6):639-49; discussion 673-81.
Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease.
Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ. University Institute of Pathology, Division of Neuropathology, University Medical School (CHUV), 1011, Lausanne, Switzerland. judmik@telus.net
The cause, or causes, of the vast majority of Alzheimer's disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD.
MeSH Terms: * Aged * Aged, 80 and over * Alzheimer Disease/genetics * Alzheimer Disease/microbiology* * Alzheimer Disease/pathology* * Atrophy/immunology * Atrophy/pathology * Base Sequence * Blotting, Western * Borrelia burgdorferi/genetics * Borrelia burgdorferi/isolation & purification* * Brain/microbiology* * Brain/pathology* * Cerebral Cortex/pathology * Chronic Disease * DNA Primers/genetics * Frontal Lobe/microbiology * Frontal Lobe/pathology * Genotype * Humans * In Situ Hybridization * Lyme Neuroborreliosis/complications* * Lyme Neuroborreliosis/genetics * Polymerase Chain Reaction * RNA, Ribosomal, 16S/analysis * RNA, Ribosomal, 16S/genetics * Research Support, Non-U.S. Gov't * Spirochaetales/genetics Substances: * DNA Primers * RNA, Ribosomal, 16S PMID: 15665404 [PubMed - indexed for MEDLINE]
ALZHEIMER - BORRELIOOSI
Valvojat: Jatta1001, Borrelioosiyhdistys, Bb
ALZHEIMER - BORRELIOOSI
Viimeksi muokannut Bb, La Maalis 07, 2009 12:59. Yhteensä muokattu 1 kertaa.
Lähettäjä: Soijuv Lähetetty: 7.2.2006 9:10
Alzheimer-diagnoosilla olevan henkilön aivokudoksesta löytyi kystamuotoisia borreliabakteereita:
Control/Tracking Number: 06-A-2798-ALZ
Activity: ICAD Conference
Current Date/Time: 2/4/2006 9:01:04 AM
Cystic Borrelia in Alzheimer's disease and in Non-Dementia Neuroborreliosis
Author Block: Alan B. MacDonald1,2, 1Columbia University, NY ,NY, Smithtown, NY, USA; 2St Catherine of Siena Medical Center,
Smithtown, NY, USA. Contact e-mail: inmacdonald@yahoo.com
Background:A cystic form for Borrelia burgdoferi (Bb) was initially reported in 1988 in an autopsy study of Alzheimer's disease
tissue obtained from Dr. George Glenner's brain bank. Cystic profiles were documented with silver stains, and with Murine
Monoclonal antibodies to a Flagellin Epitope specific for Bb and B. hermseii [H9724 from Dr Alan Barbour]
Objective(s):Fresh frozen hippocampus tissues from Alzheimer's disease cases provided by the Harvard University McLean Hospital
brain bank were cultured in BSK M medium to attempt to grow spirochetes in vitro
Methods:Triturated fresh hippocampus was cultured in vitro in sterile BSK M liquid media at 24 degrees C. for one year. Darkfield
microscopy examination and Acridine orange staining with epifluorescence microscopy was completed. Detection of specific Flagellin
DNA sequences from ORF BBO147 using a Molecular Beacon DNA probe was used to measure incremental increases in Borrelia
specific Flagellin DNA in cultures , as compared with the original fresh tissue retained uncultured DNA Extracts.
Results:Cystic borrelia structures were recovered from in vitro cultures of fresh Alzheimer disease hippocampus tissue. Incremental increases in Borrelia burgdorferi flagellin B DNA were documented in cultured tissues.
Conclusions:A subset of Alzheimer's disease is related to chronic Neuroborreliosis in the human host.
Alzheimer-diagnoosilla olevan henkilön aivokudoksesta löytyi kystamuotoisia borreliabakteereita:
Control/Tracking Number: 06-A-2798-ALZ
Activity: ICAD Conference
Current Date/Time: 2/4/2006 9:01:04 AM
Cystic Borrelia in Alzheimer's disease and in Non-Dementia Neuroborreliosis
Author Block: Alan B. MacDonald1,2, 1Columbia University, NY ,NY, Smithtown, NY, USA; 2St Catherine of Siena Medical Center,
Smithtown, NY, USA. Contact e-mail: inmacdonald@yahoo.com
Background:A cystic form for Borrelia burgdoferi (Bb) was initially reported in 1988 in an autopsy study of Alzheimer's disease
tissue obtained from Dr. George Glenner's brain bank. Cystic profiles were documented with silver stains, and with Murine
Monoclonal antibodies to a Flagellin Epitope specific for Bb and B. hermseii [H9724 from Dr Alan Barbour]
Objective(s):Fresh frozen hippocampus tissues from Alzheimer's disease cases provided by the Harvard University McLean Hospital
brain bank were cultured in BSK M medium to attempt to grow spirochetes in vitro
Methods:Triturated fresh hippocampus was cultured in vitro in sterile BSK M liquid media at 24 degrees C. for one year. Darkfield
microscopy examination and Acridine orange staining with epifluorescence microscopy was completed. Detection of specific Flagellin
DNA sequences from ORF BBO147 using a Molecular Beacon DNA probe was used to measure incremental increases in Borrelia
specific Flagellin DNA in cultures , as compared with the original fresh tissue retained uncultured DNA Extracts.
Results:Cystic borrelia structures were recovered from in vitro cultures of fresh Alzheimer disease hippocampus tissue. Incremental increases in Borrelia burgdorferi flagellin B DNA were documented in cultured tissues.
Conclusions:A subset of Alzheimer's disease is related to chronic Neuroborreliosis in the human host.
Viimeksi muokannut Bb, La Maalis 07, 2009 12:59. Yhteensä muokattu 1 kertaa.
Lähettäjä: Soijuv Lähetetty: 26.2.2006 16:16
Neuroreport. 1994 Jun 2;5(10):1201-4.
Further ultrastructural evidence that spirochaetes may play a role in the
aetiology of Alzheimer's disease.
Miklossy J, Kasas S, Janzer RC, Ardizzoni F, Van der Loos H.
University Institute of Pathology, Division of Neuropathology, Lausanne,
Switzerland.
Recently it was reported that, at autopsy, in neuropathologically confirmed
cases of Alzheimer's disease spirochaetes were found in blood and
cerebrospinal fluid using dark-field microscopy. Moreover, the spirochaetes
were isolated and cultured from brain tissue. We now show, using scanning
electron microscopy and atomic force microscopy that the helically shaped
microorganisms isolated and cultured from the Alzheimer brains possess axial
filaments. This indicates that these microorganisms taxonomically indeed
belong to the order Spirochaetales. A morphometric analysis reinforces this
notion.
PMID: 7919164 [PubMed - indexed for MEDLINE]
Neuroreport. 1994 Jun 2;5(10):1201-4.
Further ultrastructural evidence that spirochaetes may play a role in the
aetiology of Alzheimer's disease.
Miklossy J, Kasas S, Janzer RC, Ardizzoni F, Van der Loos H.
University Institute of Pathology, Division of Neuropathology, Lausanne,
Switzerland.
Recently it was reported that, at autopsy, in neuropathologically confirmed
cases of Alzheimer's disease spirochaetes were found in blood and
cerebrospinal fluid using dark-field microscopy. Moreover, the spirochaetes
were isolated and cultured from brain tissue. We now show, using scanning
electron microscopy and atomic force microscopy that the helically shaped
microorganisms isolated and cultured from the Alzheimer brains possess axial
filaments. This indicates that these microorganisms taxonomically indeed
belong to the order Spirochaetales. A morphometric analysis reinforces this
notion.
PMID: 7919164 [PubMed - indexed for MEDLINE]
Viimeksi muokannut Bb, La Maalis 07, 2009 13:00. Yhteensä muokattu 1 kertaa.
Lähettäjä: Soijuv Lähetetty: 26.2.2006 16:25
Antibioottihoito saattaa auttaa lievää tai keskivaikeaa Alzheimerin tautia sairastavia:
J Am Geriatr Soc. 2004 Mar;52(3):381-7.
A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease.
Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, McDougall A, Gnarpe J, O'DONNell M, Chernesky M.
Department of Pathology and Molecular Medicine, Biostatistics Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada.
loebm@mcmaster.ca
OBJECTIVES: To assess whether doxycycline and rifampin have a therapeutic role in patients with Alzheimer's disease (AD).
DESIGN: Randomized, triple-blind, controlled trial.
SETTING: Three tertiary care and two community geriatric clinics in Canada.
PARTICIPANTS: One hundred one patients with probable AD and mild to moderate dementia.
INTERVENTION: Oral daily doses of doxycycline 200 mg and rifampin 300 mg for 3 months.
MEASUREMENTS: The primary outcome was a change in Standardized Alzheimer's Disease Assessment Scale cognitive subscale (SADAScog) at 6 months. Secondary outcomes were changes in the SADAScog at 12 months and tests of dysfunctional behavior, depression, and functional status.
RESULTS: There was significantly less decline in the SADAScog score at 6 months in the antibiotic group than in the placebo group, (-2.75 points, 95% confidence interval (CI)=-5.28 to -0.22, P=.034). At 12 months, the difference between groups in the SADAScog was -4.31 points (95% CI=-9.17-0.56, P=.079). The antibiotic group showed significantly less dysfunctional behavior at 3 months. There was no significant difference in adverse events between groups (P=.34). There were no differences in Chlamydia pneumoniae detection using polymerase chain reaction or antibodies (immunoglobulin (Ig)G or IgA) between groups.
CONCLUSION: Therapy with doxycycline and rifampin may have atherapeutic role in patients with mild to moderate AD. The mechanism is unlikely to be due to their effect on C. pneumoniae. More research is needed to investigate these agents.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 14962152 [PubMed - indexed for MEDLINE]
Antibioottihoito saattaa auttaa lievää tai keskivaikeaa Alzheimerin tautia sairastavia:
J Am Geriatr Soc. 2004 Mar;52(3):381-7.
A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease.
Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, McDougall A, Gnarpe J, O'DONNell M, Chernesky M.
Department of Pathology and Molecular Medicine, Biostatistics Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada.
loebm@mcmaster.ca
OBJECTIVES: To assess whether doxycycline and rifampin have a therapeutic role in patients with Alzheimer's disease (AD).
DESIGN: Randomized, triple-blind, controlled trial.
SETTING: Three tertiary care and two community geriatric clinics in Canada.
PARTICIPANTS: One hundred one patients with probable AD and mild to moderate dementia.
INTERVENTION: Oral daily doses of doxycycline 200 mg and rifampin 300 mg for 3 months.
MEASUREMENTS: The primary outcome was a change in Standardized Alzheimer's Disease Assessment Scale cognitive subscale (SADAScog) at 6 months. Secondary outcomes were changes in the SADAScog at 12 months and tests of dysfunctional behavior, depression, and functional status.
RESULTS: There was significantly less decline in the SADAScog score at 6 months in the antibiotic group than in the placebo group, (-2.75 points, 95% confidence interval (CI)=-5.28 to -0.22, P=.034). At 12 months, the difference between groups in the SADAScog was -4.31 points (95% CI=-9.17-0.56, P=.079). The antibiotic group showed significantly less dysfunctional behavior at 3 months. There was no significant difference in adverse events between groups (P=.34). There were no differences in Chlamydia pneumoniae detection using polymerase chain reaction or antibodies (immunoglobulin (Ig)G or IgA) between groups.
CONCLUSION: Therapy with doxycycline and rifampin may have atherapeutic role in patients with mild to moderate AD. The mechanism is unlikely to be due to their effect on C. pneumoniae. More research is needed to investigate these agents.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 14962152 [PubMed - indexed for MEDLINE]
Viimeksi muokannut Bb, La Maalis 07, 2009 13:03. Yhteensä muokattu 2 kertaa.
Lähettäjä: Soijuv Lähetetty: 14.3.2006 14:06
Neuroborrelioosia sairastavalla henkilöllä Alzheimerin oireet.
http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum
Curr Microbiol. 2006 Mar 9; [Epub ahead of print]
Lyme Disease Associated with Alzheimer's Disease.
Meer-Scherrer L, Chang Loa C, Adelson ME, Mordechai E, Lobrinus JA, Fallon BA, Tilton RC.
Laurence Meer-Scherrer, 37 Flammat, Aumatt, Switzerland.
This case report discusses a patient with co-occurring neuroborreliosis and Alzheimer's disease (AD). Although no claim is made for causality nor is there objective evidence that spirochetes are involved in AD, co-infection may exacerbate the symptoms of either neuroborreliosis or AD. Much is to be learned about the role of spirochetes in degenerative central nervous system disease.
PMID: 16528463 [PubMed - as supplied by publisher]
Neuroborrelioosia sairastavalla henkilöllä Alzheimerin oireet.
http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum
Curr Microbiol. 2006 Mar 9; [Epub ahead of print]
Lyme Disease Associated with Alzheimer's Disease.
Meer-Scherrer L, Chang Loa C, Adelson ME, Mordechai E, Lobrinus JA, Fallon BA, Tilton RC.
Laurence Meer-Scherrer, 37 Flammat, Aumatt, Switzerland.
This case report discusses a patient with co-occurring neuroborreliosis and Alzheimer's disease (AD). Although no claim is made for causality nor is there objective evidence that spirochetes are involved in AD, co-infection may exacerbate the symptoms of either neuroborreliosis or AD. Much is to be learned about the role of spirochetes in degenerative central nervous system disease.
PMID: 16528463 [PubMed - as supplied by publisher]
Viimeksi muokannut Bb, La Maalis 07, 2009 13:04. Yhteensä muokattu 1 kertaa.
Lähettäjä: Soijuv Lähetetty: 20.3.2006 8:14
Borrelioosissa ja ALzheimerissa on tavattu samankaltaisia muutoksia immuunijärjestelmän toiminnassa, erityisesti tulehdussytokiineissä jotka vaikuttavat esim. tryptofaanin aineenvaihduntaan kynureniini reitin kautta. Tällöin muodostuu mm. keskushermostomyrkkyä (kinoliinihappo) joka on on osallisena useissa keskushermostosairauksissa. Seuraavassa itävaltalaisia ja australialaisia tutkimuksia asiasta:
Eur J Clin Chem Clin Biochem. 1994 Sep;32(9):685-9.
Neopterin Production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy.
Gasse T, Meyersbach P, Schmutzhard E, Wachter H, Fuchs D
Klinik fur Neurologie, Universitat Innsbruck, Austria.
Fourteen patients with Borrelia burgdorferi infection were investigated for possible abnormalities of tryptophan and neopterin metabolism. Four patients (2 were investigated before therapy, 2 when therapy had been already started) had acute Lyme neuroborreliosis, and 10 patients were investigated months to years after an acute infection. Increased concentrations of neopterin and of the tryptophan-degradation product, L-kynurenine, were detected in the cerebrospinal fluid of patients with acute Lyme neuroborreliosis; one patient presented with subnormal tryptophan. Similar but less marked changes were seen in the treated patients and in some of the patients with Lyme encephalopathy. No such abnormalities were seen in the serum of the patients. The data indicate a role of the immune system and particularly of endogenously formed cytokines, like interferon-gamma and tumour necrosis factor-alpha, effecting tryptophan and neopterin metabolism in patients with acute Lyme neuroborreliosis.
Redox Rep. 2002;7(4):199-206.
Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease.
Guillemin GJ, Brew B
Centre for Immunology and Department of Neurology, St Vincent's Hospital and University of New South Wales, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide. Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease. Recently, we demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of QUIN, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of QUIN toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease.
Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.
Publication Types:
· Review
PMID: 12396664 [PubMed - indexed for MEDLINE]
Adv Exp Med Biol. 2003;527:167-76.
Quinolinic acid in the pathogenesis of Alzheimer's disease.
Guillemin GJ, Williams KR, Smith DG, Smythe GA, Croitoru-Lamoury J, Brew BJ
Centre for Immunology, St Vincent's Hospital, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
We propose that the tryptophan catabolites produced through the kynurenine pathway (KP), and more particularly quinolinic acid (QUIN), may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we demonstrated that after 72 hours amyloid peptide (Abeta) 1-42 induced indoleamine 2,3-dioxygenase (IDO) expression and in a significant increase in production of QUIN by human macrophages and microglia. In contrast, Abeta11-40 and Prion peptide (PrP) 106-126 did not induce any significant increase in QUIN production. We also investigated the potential modulatory effect of QUIN and kynurenic acid (KYNA) on Abeta11-42 and Abeta1-40 aggregation. After 24 and 120 hours, we did not observe any significant difference in the level of aggregation compared to the control (Abeta alone). Abeta has been shown to induce IL1-beta mRNA expression by human foetal astrocytes and macrophages. We demonstrate that QUIN has the same effect. Interestingly, IL-1beta has been found in association with plaques in AD. All together these data imply that QUIN may be, locally, one of the factors involved in the pathogenesis of neuronal damage in AD.
PMID: 15206729 [PubMed - indexed for MEDLINE]
J Neural Transm.2000;107(3):343-53.
Tryptophan degradation and immune activation in Alzheimer's disease.
Widner B, Leblhuber F, Walli J , Tilz GP, Demel U, Fuchs D
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Alzheimer's disease (AD) is likely associated with systemic immune activation. During immune response, interferon-gamma stimulates indoleamine 2,3-dioxygenase (IDO) converting tryptophan to N-formylkynurenine followed by kynurenine in an ensuing step. Thus, IDO activity is estimated by the kynurenine per tryptophan quotient (Kyn/Trp). In 21 patients suffering from AD, in 20 controls of similar age, and in 49 blood donors we measured serum tryptophan and kynurenine concentrations by HPLC. Lower tryptophan concentrations were found in elderly control subjects compared to blood donors (62.1 vs. 73.0 microM, p < 0.005). Tryptophan concentrations tended to be still lower in AD patients (54.4 microM, p = 0.07) compared to elderly controls. Enhanced tryptophan degradation in patients was reflected by significantly increased Kyn/Trp (46.1 vs. 34.1 in elderly controls, p < 0.05). Correlations were found in patients between Kyn/Trp and concentrations of soluble immune markers in serum, i.e., neopterin, interleukin-2 receptor and tumor necrosis factor receptor (all p < 0.001). Increased Kyn/Trp was associated with reduced cognitive performance. Tryptophan degradation due to immune activation may exert impact on the pathogenesis of AD.
PMID: 10821443 [PubMed - indexed for MEDLINE]
Borrelioosissa ja ALzheimerissa on tavattu samankaltaisia muutoksia immuunijärjestelmän toiminnassa, erityisesti tulehdussytokiineissä jotka vaikuttavat esim. tryptofaanin aineenvaihduntaan kynureniini reitin kautta. Tällöin muodostuu mm. keskushermostomyrkkyä (kinoliinihappo) joka on on osallisena useissa keskushermostosairauksissa. Seuraavassa itävaltalaisia ja australialaisia tutkimuksia asiasta:
Eur J Clin Chem Clin Biochem. 1994 Sep;32(9):685-9.
Neopterin Production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy.
Gasse T, Meyersbach P, Schmutzhard E, Wachter H, Fuchs D
Klinik fur Neurologie, Universitat Innsbruck, Austria.
Fourteen patients with Borrelia burgdorferi infection were investigated for possible abnormalities of tryptophan and neopterin metabolism. Four patients (2 were investigated before therapy, 2 when therapy had been already started) had acute Lyme neuroborreliosis, and 10 patients were investigated months to years after an acute infection. Increased concentrations of neopterin and of the tryptophan-degradation product, L-kynurenine, were detected in the cerebrospinal fluid of patients with acute Lyme neuroborreliosis; one patient presented with subnormal tryptophan. Similar but less marked changes were seen in the treated patients and in some of the patients with Lyme encephalopathy. No such abnormalities were seen in the serum of the patients. The data indicate a role of the immune system and particularly of endogenously formed cytokines, like interferon-gamma and tumour necrosis factor-alpha, effecting tryptophan and neopterin metabolism in patients with acute Lyme neuroborreliosis.
Redox Rep. 2002;7(4):199-206.
Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease.
Guillemin GJ, Brew B
Centre for Immunology and Department of Neurology, St Vincent's Hospital and University of New South Wales, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide. Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease. Recently, we demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of QUIN, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of QUIN toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease.
Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.
Publication Types:
· Review
PMID: 12396664 [PubMed - indexed for MEDLINE]
Adv Exp Med Biol. 2003;527:167-76.
Quinolinic acid in the pathogenesis of Alzheimer's disease.
Guillemin GJ, Williams KR, Smith DG, Smythe GA, Croitoru-Lamoury J, Brew BJ
Centre for Immunology, St Vincent's Hospital, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
We propose that the tryptophan catabolites produced through the kynurenine pathway (KP), and more particularly quinolinic acid (QUIN), may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we demonstrated that after 72 hours amyloid peptide (Abeta) 1-42 induced indoleamine 2,3-dioxygenase (IDO) expression and in a significant increase in production of QUIN by human macrophages and microglia. In contrast, Abeta11-40 and Prion peptide (PrP) 106-126 did not induce any significant increase in QUIN production. We also investigated the potential modulatory effect of QUIN and kynurenic acid (KYNA) on Abeta11-42 and Abeta1-40 aggregation. After 24 and 120 hours, we did not observe any significant difference in the level of aggregation compared to the control (Abeta alone). Abeta has been shown to induce IL1-beta mRNA expression by human foetal astrocytes and macrophages. We demonstrate that QUIN has the same effect. Interestingly, IL-1beta has been found in association with plaques in AD. All together these data imply that QUIN may be, locally, one of the factors involved in the pathogenesis of neuronal damage in AD.
PMID: 15206729 [PubMed - indexed for MEDLINE]
J Neural Transm.2000;107(3):343-53.
Tryptophan degradation and immune activation in Alzheimer's disease.
Widner B, Leblhuber F, Walli J , Tilz GP, Demel U, Fuchs D
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Alzheimer's disease (AD) is likely associated with systemic immune activation. During immune response, interferon-gamma stimulates indoleamine 2,3-dioxygenase (IDO) converting tryptophan to N-formylkynurenine followed by kynurenine in an ensuing step. Thus, IDO activity is estimated by the kynurenine per tryptophan quotient (Kyn/Trp). In 21 patients suffering from AD, in 20 controls of similar age, and in 49 blood donors we measured serum tryptophan and kynurenine concentrations by HPLC. Lower tryptophan concentrations were found in elderly control subjects compared to blood donors (62.1 vs. 73.0 microM, p < 0.005). Tryptophan concentrations tended to be still lower in AD patients (54.4 microM, p = 0.07) compared to elderly controls. Enhanced tryptophan degradation in patients was reflected by significantly increased Kyn/Trp (46.1 vs. 34.1 in elderly controls, p < 0.05). Correlations were found in patients between Kyn/Trp and concentrations of soluble immune markers in serum, i.e., neopterin, interleukin-2 receptor and tumor necrosis factor receptor (all p < 0.001). Increased Kyn/Trp was associated with reduced cognitive performance. Tryptophan degradation due to immune activation may exert impact on the pathogenesis of AD.
PMID: 10821443 [PubMed - indexed for MEDLINE]
Viimeksi muokannut Bb, La Maalis 07, 2009 13:12. Yhteensä muokattu 1 kertaa.
Lähettäjä: Soijuv Lähetetty: 20.3.2006 8:37
Samoja neopteriini (liikatuotanto)/tryptofaaniongelmia (määrän väheneminen) on löydetty useiden muidenkin sairauksien kohdalla mm. masennuksen, Parkinsonin taudin jne. Immuunijärjestelmän saaminen tasapainoon näyttää olevan ensiarvoisen tärkeää mikäli taudit halutaan saada kuriin - miten se tapahtuu? Olisikohan syytä tarkastella uudelleen myös masennuksen hoito-ohjeita? Syynä ei ehkä olekaan ihmissuhdeongelmat, työuupumus jne. Tryptofaani on yksi aminohapoista ja sitä on erityisen paljon esim. banaaneissa. Natura Median sivuilta löytyi seuraava selvitys: "TRYPTOFAANI ja mieli":
Tryptofaani on tarpeellinen aivojen välittäjäaineen serotoniinin (enteramiini), noradrenaliinin ja melatoniinin muodostumiseksi, joten tryptofaanilla on tärkeä merkitys mielialatasapainoon, masennusherkkyyteen ja unen virkistävyyteen.
Serotoniini pystyy varastoitumaan verihiutaleisiin ja vapautumaan tarpeen mukaan. Siksi tryptofaanin toimintapareilla B6-vitamiinilla, niasiinilla, B1-vitamiinilla ja B12-vitamiinilla tryptofaanin ohella on erityisen suotuisa vaikutus tapauksissa, joissa keskittymiskyky, mieliala ja univalmius on häiriintynyt.
Edellä mainitulla yhdistelmällä on seuraavia suotuisia vaikutuksia: - auttaa lisäämään aivojen serotoniiniaktiivisuutta - ehkäisemään masennusta - parantamaan keskittymistä - lisäämään huomiokykyä - kohentamaan mielialaa, - parantamaan aivosolujen välistä toimintaa - syventämään unen laatua - parantamaan univalmiutta.
Tutkimus masennuksen yhteydestä em. tulehdusvälittäjäaine-/neopteriini-, tryptofaaniongelmiin:
Brain Behav Immun. 2002 Oct;16(5):590-5.
Neopterin production, tryptophan degradation, and mental depression--what is the link?
Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D.
Institute of Medical Chemistry and Biochemistry, University of Innsbruck,
Fritz Pregl Strasse 3, Innsbruck A-6020, Austria.
The cytokine interferon-gamma stimulates human monocytes/macrophages to release large amounts of neopterin.
Increased neopterin concentrations in body fluids of patients are observed during diseases with activated cellular (=TH1-type) immune response such as allograft rejection, virus infections, autoimmune disorders, or malignant tumors but also in neurodegenerative diseases or during pregnancy. In various cells interferon-gamma induces indoleamine 2,3-dioxygenase (IDO) which degrades tryptophan via the kynurenine pathway. Therefore like increased neopterin formation, enhanced tryptophan degradation is observed in diseases concomitant with cellular immune activation. Disturbed metabolism of tryptophan affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it appears to be associated with an increased susceptibility for depression.
In fact, enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryptophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases. Activation of IDOcould represent an important link between the immunological network and the pathogenesis of depression.
Publication Types:
Review
PMID: 12401473 [PubMed - indexed for MEDLINE]
Samoja neopteriini (liikatuotanto)/tryptofaaniongelmia (määrän väheneminen) on löydetty useiden muidenkin sairauksien kohdalla mm. masennuksen, Parkinsonin taudin jne. Immuunijärjestelmän saaminen tasapainoon näyttää olevan ensiarvoisen tärkeää mikäli taudit halutaan saada kuriin - miten se tapahtuu? Olisikohan syytä tarkastella uudelleen myös masennuksen hoito-ohjeita? Syynä ei ehkä olekaan ihmissuhdeongelmat, työuupumus jne. Tryptofaani on yksi aminohapoista ja sitä on erityisen paljon esim. banaaneissa. Natura Median sivuilta löytyi seuraava selvitys: "TRYPTOFAANI ja mieli":
Tryptofaani on tarpeellinen aivojen välittäjäaineen serotoniinin (enteramiini), noradrenaliinin ja melatoniinin muodostumiseksi, joten tryptofaanilla on tärkeä merkitys mielialatasapainoon, masennusherkkyyteen ja unen virkistävyyteen.
Serotoniini pystyy varastoitumaan verihiutaleisiin ja vapautumaan tarpeen mukaan. Siksi tryptofaanin toimintapareilla B6-vitamiinilla, niasiinilla, B1-vitamiinilla ja B12-vitamiinilla tryptofaanin ohella on erityisen suotuisa vaikutus tapauksissa, joissa keskittymiskyky, mieliala ja univalmius on häiriintynyt.
Edellä mainitulla yhdistelmällä on seuraavia suotuisia vaikutuksia: - auttaa lisäämään aivojen serotoniiniaktiivisuutta - ehkäisemään masennusta - parantamaan keskittymistä - lisäämään huomiokykyä - kohentamaan mielialaa, - parantamaan aivosolujen välistä toimintaa - syventämään unen laatua - parantamaan univalmiutta.
Tutkimus masennuksen yhteydestä em. tulehdusvälittäjäaine-/neopteriini-, tryptofaaniongelmiin:
Brain Behav Immun. 2002 Oct;16(5):590-5.
Neopterin production, tryptophan degradation, and mental depression--what is the link?
Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D.
Institute of Medical Chemistry and Biochemistry, University of Innsbruck,
Fritz Pregl Strasse 3, Innsbruck A-6020, Austria.
The cytokine interferon-gamma stimulates human monocytes/macrophages to release large amounts of neopterin.
Increased neopterin concentrations in body fluids of patients are observed during diseases with activated cellular (=TH1-type) immune response such as allograft rejection, virus infections, autoimmune disorders, or malignant tumors but also in neurodegenerative diseases or during pregnancy. In various cells interferon-gamma induces indoleamine 2,3-dioxygenase (IDO) which degrades tryptophan via the kynurenine pathway. Therefore like increased neopterin formation, enhanced tryptophan degradation is observed in diseases concomitant with cellular immune activation. Disturbed metabolism of tryptophan affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it appears to be associated with an increased susceptibility for depression.
In fact, enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryptophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases. Activation of IDOcould represent an important link between the immunological network and the pathogenesis of depression.
Publication Types:
Review
PMID: 12401473 [PubMed - indexed for MEDLINE]