Alzheimer Disease: Grubeck-Loebenstein B

Blasko I, Grubeck-Loebenstein B. · No affiliation provided · Wien Klin Wochenschr. · Pubmed #12793027 No free full text.

This publication has no abstract.

Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. · Department of Psychiatry, University Hospital of Innsbruck, Innsbruck, Austria. · Aging Cell. · Pubmed #15268750 No free full text.

Abstract: A huge amount of evidence has implicated amyloid beta (A beta) peptides and other derivatives of the amyloid precursor protein (beta APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a role in the development of neurodegeneration. Little is known, however, about the molecular mechanisms that underlie age-related changes of innate immunity and how they affect brain pathology. Aging is characteristically accompanied by a shift within innate immunity towards a pro-inflammatory status. Pro-inflammatory mediators such as tumour necrosis factor-alpha or interleukin-1 beta can then in combination with interferon-gamma be toxic on neurons and affect the metabolism of beta APP such that increased concentrations of amyloidogenic peptides are produced by neuronal cells as well as by astrocytes. A disturbed balance between the production and the degradation of A beta can trigger chronic inflammatory processes in microglial cells and astrocytes and thus initiate a vicious circle. This leads to a perpetuation of the disease.

Wick G, Berger P, Jansen-Dürr P, Grubeck-Loebenstein B. · Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. · Exp Gerontol. · Pubmed #12543257 No free full text.

Abstract: Humans and animals are structurally designed as a compromise to guarantee optimal survival until the time of reproduction based on natural selection that is effective until that age. Modern conditions of life including improvement of hygiene, preventive and curative medicine as well as socio-economic and political developments have led to an increase of the mean life expectancy that allows ever larger proportions of the population to reach an age that is far beyond that of the reproductive phase. The concept of a Darwinian-evolutionary basis for the development of age-related diseases in principle postulates that genetic traits that are beneficial in younger years to allow for successful reproduction may become deleterious in the elderly, i.e. when selective pressure does not seem to be effective anymore. Examples for this mechanism of pleiotropic antagonism taken from the work of the Institute for Biomedical Aging Research in Innsbruck, Austria, include atherosclerosis, benign and malignant prostate hypertrophy, Alzheimer's disease and the reciprocal relationship between cellular senescence and cancer.

Blasko I, Grubeck-Loebenstein B. · Department of Psychiatry, University Hospital of Innsbruck, Austria. · Drugs Aging. · Pubmed #12534311 No free full text.

Abstract: The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered.

Blasko I, Ransmayr G, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. · Department of Neurology, University Hospital of Innsbruck, Innsbruck, Austria. · J Neuroimmunol. · Pubmed #11311323 No free full text.

This publication has no abstract.

Wick G, Jansen-Dürr P, Berger P, Blasko I, Grubeck-Loebenstein B. · Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, 6020, Innsbruck, Austria. · Vaccine. · Pubmed #10689131 No free full text.

Abstract: By definition, diseases of aging become clinically manifested in elderly patients. However, their pathogenetic basis has to be sought earlier in life. The general thread of this presentation relies on the concept of an evolutionary-Darwinian view of the development of age-related diseases. In essence, this concept states that we may have to "pay" for genetic traits that play a beneficial role earlier in life by the later development of diseases since there is no post-reproductive selective pressure that may have eliminated the potential late onset detrimental effects of such genes. Examples for this kind of trade-off are taken from diseases involving the immune system (infections), the endocrine system (andropause), the nervous system (Alzheimer's disease), the locomoter system (osteoporosis), the cardio-vascular system (atherosclerosis) and cancer.

Marx F, Blasko I, Grubeck-Loebenstein B. · Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck. · Arch Immunol Ther Exp (Warsz). · Pubmed #10483867 No free full text.

Abstract: The immune system may play an important role in the neurodegenerative process in Alzheimer's disease (AD). Complement components, eicosanoids and cytokines are found in cerebral amyloid plaques. These inflammatory proteins may stimulate the amyloid beta (Abeta) production, support its aggregation and increase its cytotoxicity, thus aggrevating the pathology of AD. Abeta may trigger their release from activated microglia and astrocytes which are the main sources of these proteins. However, there are also indications for a protective role of the immune system against the development of AD. Microglial cells have been shown to degrade Abeta and recent evidence suggests a role of autoreactive Abeta-specific T cells in the elimination of the peptide. This mechanism seems to be impaired in the majority of patients with AD. An Abeta-specific immune reaction may thus represent a natural defence mechanism directed against the accumulation of dangerous amyloidogenic substances. Impairment of the immune system and the failure to eliminate a toxic metabolite can be the basis for a chronic non-specific inflammatory process in the brain, as described above. AD is a good example how an immune response may lead to tissue destruction and neuronal loss instead of maintaining the integrity of the body.

Blasko I, Apochal A, Boeck G, Hartmann T, Grubeck-Loebenstein B, Ransmayr G. · Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria. · Neurobiol Dis. · Pubmed #11741404 No free full text.

Abstract: Trying to decrease the production of Amyloid beta (Abeta) has been envisaged as a promising approach to prevent neurodegeneration in Alzheimer's disease (AD). A chronic inflammatory reaction with activated microglia cells and astrocytes is a constant feature of AD. The participation of the immune system in the disease process is further documented in several retrospective clinical studies showing an inverse relationship between the prevalence of AD and nonsteroidal anti-inflammatory drug (NSAID) therapy. Previously, we demonstrated that the combination of the proinflammatory cytokines TNFalpha with IFNgamma induces the production of Abeta-42 and Abeta-40 in human neuronal cells. In the present study, the neuronal cell line Sk-n-sh was incubated for 12 h with the cyclooxygenase inhibitor ibuprofen and subsequently stimulated with the cytokines TNFalpha and IFNgamma. Ibuprofen treatment decreased the secretion of total Abeta in the conditioned media of cytokine stimulated cells by 50% and prevented the accumulation of Abeta-42 and Abeta-40 in detergent soluble cell extracts. Viability of neuronal cells measured by detection of apoptosis was neither influenced by ibuprofen nor by cytokine treatment. The reduction in the production of Abeta by ibuprofen was presumably due to a decreased production of betaAPP, which in contrast to the control proteins M2 pyruvate kinase, beta-tubulin and the cytokine inducible ICAM-1 was detected at low concentration in ibuprofen treated cells. The data demonstrate a possible mechanism how ibuprofen may decrease the risk and delay the onset of AD.

Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B. · Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria. · Neurobiol Dis. · Pubmed #11114266 No free full text.

Abstract: Chronic inflammation and astrocytosis are characteristic histopathological features of Alzheimer's Disease (AD). Astrocytes are one of the predominant cell types in the brain. In AD they are activated and produce inflammatory components such as complement components, acute phase proteins, and cytokines. In this study we analyzed the effect of cytokines on the production of amyloid beta (Abeta) in the astrocytoma cell line U373 and in primary human astrocytes isolated postmortem from healthy aged persons as well as from patients with AD. Astrocytes did not produce Abeta in the absence of stimuli or following stimulation with IL-1beta, TNFalpha, IL-6, and TGF-beta1. Neither did combinations of TNFalpha and IL-1beta, IL-6 or TGF-beta1, or the coadministration of IFNgamma and IL-6 or TGF-beta1 induce Abeta production. In contrast, pronounced production of Abeta1-40 and Abeta1-42 was observed when primary astrocytes or astrocytoma cells were stimulated with combinations of IFNgamma and TNFalpha or IFNgamma and IL-1beta. Induction of Abeta production was accompanied by decreased glycosylation of APP as well as by increased secretion of APPsbeta. Our results suggest that astrocytes may be an important source of Abeta in the presence of certain combinations of inflammatory cytokines. IFNgamma in combination with TNFalpha or IL-1beta seems to trigger Abeta production by supporting beta-secretase cleavage of the immature APP molecule.

Marx F, Blasko I, Zisterer K, Grubeck-Loebenstein B. · Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck. · Exp Gerontol. · Pubmed #10579638 No free full text.

Abstract: The ubiquitously expressed Alzheimer amyloid precursor protein (APP) has raised wide interest in view of its connection with Alzheimer's disease. We now provide a novel extraneuronal cell model in which human Epstein-Barr virus transformed B cells that constitutively hardly produce APP are transfected with wild-type or mutated APP695, harboring the Swedish mutation APPsw, or a dilysine endoplasmic reticulum retrieval motif--APP(ER). This leads to the generation of three types of cells, one with a high secretion of soluble APPs but low levels of intracellular APP, another with a high intracellular APP retention but a low APP secretion, and a third in which APP maturation and secretion are strongly impaired. The suitability of our cell model for various purposes is proven by its usage in different systems. We demonstrate that it is a useful tool for studies on the physiology of APPs and represents a good model system to analyze the cellular mechanisms of Abeta-directed autoimmune reactivity.

Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B. · a Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria. · FASEB J. · Pubmed #9872930 links to  free full text

Abstract: The appearance of inflammatory markers associated with amyloid plaques indicates a state of chronic inflammation in Alzheimer's disease (AD). Multiple epidemiological studies also suggest that patients taking anti-inflammatory drugs have a decreased risk of developing AD. Here we present evidence that inflammatory cytokines can alter the metabolism of the beta-amyloid precursor protein (betaAPP). We show that the combination of tumor necrosis factor alpha and interferon gamma triggers the production of beta-amyloid peptides and inhibits the secretion of soluble APPs by human neuronal and extraneuronal cells. The results demonstrate a new mechanism by which inflammatory components can exacerbate the fundamental pathology in AD.

Grubeck-Loebenstein B, Blasko I, Marx FK, Trieb I. · No affiliation provided · Trends Neurosci. · Pubmed #10675914 No free full text.

This publication has no abstract.

Blasko I, Marx F, Grubeck-Loebenstein B, Marksteiner J. · No affiliation provided · Arch Neurol. · Pubmed #10404994 links to  free full text

This publication has no abstract.