Alzheimer Disease: Hartmann T

Tschäpe JA, Hartmann T. · Centre for Molecular Biology Heidelberg (ZMBH), INF 282, D-69120 Heidelberg, Germany. · Recent Pat CNS Drug Discov. · Pubmed #18221198 No free full text.

Abstract: It is now almost a century ago that Alois Alzheimer first presented his results in public. Main characteristics of Alzheimer's disease (AD) are massive cerebral accumulation of amyloid, composed of fibrillary aggregates of the Amyloid beta peptide (Abeta) and intracellular accumulation of abnormally phosphorylated tau protein associated with widespread neurodegeneration. The clinical picture is characterized by progressive and irreversible dementia, which is eventually fatal. To date, there is no cure for this severe disease affecting more than of 30 million individuals worldwide. In the last decades, the treatment of Alzheimer patients was mainly focusing on symptomatical strategies. Based on the augmented knowledge about the mechanisms underlying the pathology of AD, particularly the molecular causes and consequences of AD, different therapeutic approaches arose and recently, treatment with Statins, NSAIDs and Abeta vaccines reached the level of clinical trials, showing some indication of efficacy already. According to actual evaluations, these approaches have realistic chances to become established as therapeutic routine in AD within the next 10 years. We will review here some of the most promising novel approaches to cure and prevent rather than to treat the symptoms of AD.

Hartmann T, Kuchenbecker J, Grimm MO. · Universität des Saarlandes, Uniklinikum Homburg, Neurobiologie, Homburg, Germany. · J Neurochem. · Pubmed #17986151 No free full text.

Abstract: Alzheimer's disease is the most common neurodegenerative disorder. This short review summarizes the current knowledge about the role of lipids, especially cholesterol, sphingolipids, plasmalogens, and polyunsaturated fatty acids in Alzheimer's disease etiology, pathogenesis, risk-factors, prevention, treatment, and the function of the amyloid precursor protein and the amyloid peptides in lipid homeostasis.

Grimm MO, Grimm HS, Hartmann T. · Universität des Saarlandes, Kirrberger Str. 61.4, D-66421 Homburg, Germany. · Trends Mol Med. · Pubmed #17644432 No free full text.

Abstract: The beta-amyloid peptide (A beta) is widely considered to be the molecule that causes Alzheimer's disease (AD). Besides this pathological function of A beta, recently published data reveal that A beta also has an essential physiological role in lipid homeostasis. Cholesterol increases A beta production, and conversely A beta production causes a decrease in cholesterol synthesis. The latter appears to be mediated by the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), a key enzyme in cholesterol synthesis, in an action similar to that of statins. Moreover, A beta regulates sphingolipid metabolism by directly activating sphingomyelinases (SMases). This review summarizes the molecular basis for the known physiological functions of A beta and amyloid precursor protein (APP), the roles of A beta and APP in lipid homeostasis and the medical implications of addressing lipid homeostasis in respect to AD. This knowledge might provide new insights for current and future therapeutic approaches to AD.

Zinser EG, Hartmann T, Grimm MO. · Universität des Saarlandes, Uniklinikum Homburg, Neurobiologie, Neurologie, Gebäude 90, 66421 Homburg/Saar, Germany. · Biochim Biophys Acta. · Pubmed #17418089 No free full text.

Abstract: Lipids play an important part as risk or protective factors for Alzheimer's disease. This review summarizes the current findings in which lipids influence Alzheimer's disease and introduces the molecular mechanism how these lipids are linked to amyloid production. Besides the pathological impact of amyloid in Alzheimer's disease, amyloid has a physiological function in regulating lipid homeostasis in return. The understanding of the resulting regulatory cycles between amyloid precursor protein processing and lipids provides a platform for the development of new causal therapeutic approaches for Alzheimer's disease.

Hartmann T. · Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany. · Neurodegener Dis. · Pubmed #17047372 No free full text.

Abstract: Lipids play an important part as risk factors for Alzheimer's disease. This article summarizes the current understanding of the molecular mechanism by which amyloid-beta (Abeta) peptides regulate cholesterol and sphingomyelin metabolism, and how in return cholesterol and sphingomyelin regulate Abeta peptide production. An understanding of the physiological function of amyloid precursor protein processing and Abeta function is critical for the development of future therapeutic approaches, e.g. statin treatment.

Hartmann T. · Center for Molecular Biology Heidelberg (ZMBH), University of Heidelberg, Germany. · Trends Neurosci. · Pubmed #11881745 No free full text.

Abstract: Statins have been used for many years for the treatment of hypercholesterolemia. They lower low-density lipoprotein (LDL) cholesterol, increase high-density lipoprotein (HDL) levels and are considered to be very safe. Recently, a set of potential new applications was identified for statins. In the future, these drugs could be used to treat Alzheimer's disease (AD). Past studies have suggested a link between AD and lipids and a series of reports has recently been published that significantly tightens this link and also provides some explanations at the cellular level. This review focuses on these recent developments and perspectives that appear to link cholesterol, beta-amyloid and AD.

Bayer TA, Wirths O, Majtényi K, Hartmann T, Multhaup G, Beyreuther K, Czech C. · Department of Psychiatry, University of Bonn Medical Center, Germany. · Brain Pathol. · Pubmed #11145195 No free full text.

Abstract: During the last years it has become evident that the beta-amyloid (Abeta) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). The source and place of the neurotoxic action of Abeta, however, is still a matter of controversy. The precursor of the beta-amyloid peptide is the predominantly neuronal beta-amyloid precursor protein. We, and others, hypothesize that intraneuronal misregulation of APP leads to an accumulation of Abeta peptides in intracellular compartments. This accumulation impairs APP trafficking, which starts a cascade of pathological changes and causes the pyramidal neurons to degenerate. Enhanced Abeta secretion as a function of stressed neurons and remnants of degenerated neurons provide seeds for extracellular Abeta aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia. Beta-amyloid precursor protein has a pivotal role in Alzheimer's disease.

Hartmann T. · Center for Molecular Biology (ZMBH), University of Heidelberg, Germany. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #10653285 No free full text.

Abstract: Strong evidence links excess production of a small peptide and the pathogenesis of Alzheimer's disease (AD). Originally this peptide, beta-amyloid 42 (Abeta42), was assumed to be released by a pathogenic event; it is now well established that Abeta42 is released from cells during normal cellular metabolism of the Alzheimer amyloid precursor protein. Recently, in a series of surprising reports it was discovered that Abeta42 is produced intracellularly, and what might have been regarded first as a strange abnormality of a few selected cell lines has now been recognized as an important cellular pathway for Abeta production. Moreover, the differences between secretory and intracellular Abeta production might hold the clues for brain specificity and cellular mechanisms of AD pathogenesis.

Simons M, Schwärzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB. · Department of Neurology, University of Tübingen, Germany. · Ann Neurol. · Pubmed #12205648 No free full text.

Abstract: In a randomized, placebo-controlled, double-blind study, we investigated whether statins alter cholesterol metabolites and reduce Abeta levels in the cerebrospinal fluid of 44 patients with Alzheimer's disease. Individuals were given up to 80mg simvastatin daily or placebo for 26 weeks. Overall, simvastatin did not significantly alter cerebrospinal fluid levels of Abeta40 and Abeta42. In post hoc analysis, simvastatin significantly decreased Abeta40 levels in the cerebrospinal fluid of patients with mild Alzheimer's disease. The reduction of Abeta40 correlated with the reduction of 24S-hydroxycholesterol. These changes were not observed in more severely affected patients.

Schonknecht P, Pantel J, Werle E, Hartmann T, Essig M, Baudendistel K, Beyreuther K, Schroder J. · Sektion Gerontopsychiatrie, Psychiatrische Klinik der Universitat Heidelberg. · Fortschr Neurol Psychiatr. · Pubmed #11103680 No free full text.

Abstract: Tau protein concentration in cerebrospinal fluid was determined in 55 patients with Alzheimer's disease (AD), 18 patients with vascular dementia (VD), 19 patients with dementia caused by other disorders and 14 patients with major depression. Significantly (p < 0.05) elevated protein tau concentrations were found in AD patients (564.5 +/- 275.5 pg/ml) compared to all other patient groups (VD: 406.5 +/- 263.9 pg/ml; other dementia: 275.0 +/- 135.4 pg/ml; depression: 212.9 +/- 115.6 pg/ml). However, tau levels in AD patients covered a broad range (163.2 pg/ml-1200 pg/ml). AD patients with tau levels below the 25%-percentile of the distribution (among them a high percentage of patients with presenile onset) showed tau levels similar to those of the patients with late life depression. No significant correlations between tau levels and clinical variables such as severity of dementia, age, age of onset, duration of illness, and cerebral changes as assessed by volumetric magnetic resonance imaging could be demonstrated. Similarly, we could not find an influence of either APO-E genotype or psychotropic medication on the tau levels in AD patients. In accordance with other studies our results confirm elevated tau levels in AD compared to elderly not demented control subjects. Comparing groups, this finding applies as well with respect to VD and other dementing disorders. However, elevated tau levels cannot be detected in a subgroup of AD patients. This finding needs to be further investigated in future studies.

Verwey NA, van der Flier WM, Blennow K, Clark C, Sokolow S, De Deyn PP, Galasko D, Hampel H, Hartmann T, Kapaki E, Lannfelt L, Mehta PD, Parnetti L, Petzold A, Pirttila T, Saleh L, Skinningsrud A, Swieten JC, Verbeek MM, Wiltfang J, Younkin S, Scheltens P, Blankenstein MA. · Department of Clinical Chemistry, VU University Medical Center, , HV, The Netherlands. · Ann Clin Biochem. · Pubmed #19342441 No free full text.

Abstract: BACKGROUND: Different cerebrospinal fluid (CSF) amyloid-beta 1-42 (Abeta(1-42)), total Tau (Tau) and Tau phosphorylated at threonine 181 (P-Tau) levels are reported, but currently there is a lack of quality control programmes. The aim of this study was to compare the measurements of these CSF biomarkers, between and within centres. METHODS: Three CSF-pool samples were distributed to 13 laboratories in 2004 and the same samples were again distributed to 18 laboratories in 2008. In 2004 six laboratories measured Abeta(1-42), Tau and P-Tau and seven laboratories measured one or two of these marker(s) by enzyme-linked immunosorbent assays (ELISAs). In 2008, 12 laboratories measured all three markers, three laboratories measured one or two marker(s) by ELISAs and three laboratories measured the markers by Luminex. RESULTS: In 2004, the ELISA intercentre coefficients of variance (interCV) were 31%, 21% and 13% for Abeta(1-42), Tau and P-Tau, respectively. These were 37%, 16% and 15%, respectively, in 2008. When we restricted the analysis to the Innotest (N = 13) for Abeta(1-42), lower interCV were calculated (22%). The centres that participated in both years (N = 9) showed interCVs of 21%, 15% and 9% and intra-centre coefficients (intraCV) of variance of 25%,18% and 7% in 2008. CONCLUSIONS: The highest variability was found for Abeta(1-42). The variabilities for Tau and P-Tau were lower in both years. The centres that participated in both years showed a high intraCV comparable to their interCV, indicating that there is not only a high variation between but also within centres. Besides a uniform standardization of (pre)analytical procedures, the same assay should be used to decrease the inter/intracentre variation.

Uhrig M, Brechlin P, Jahn O, Knyazev Y, Weninger A, Busia L, Honarnejad K, Otto M, Hartmann T. · Center for Molecular Biology of the University of Heidelberg, Heidelberg, Germany. · BMC Med. · Pubmed #19087254 links to  free full text

Abstract: BACKGROUND: Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several beta-amyloid peptides (Abeta) are generated. In contrast to the form with 40 amino acids (Abeta40), the variant with 42 amino acids (Abeta42) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Abeta effects have been studied extensively, little is known about specific genome-wide effects triggered by Abeta42 or Abeta40 derived from their direct precursor C99. METHODS: A combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Abeta peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference. RESULTS: Here we studied the transcriptomic and proteomic responses to increased or decreased Abeta42 and Abeta40 levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Abeta42- and Abeta40-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Abeta42/Abeta40 ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Abeta42/Abeta40 ratio, whereas a decreased ratio did not result in up-regulation of CRABP1. CONCLUSION: We conclude that increasing the Abeta42/Abeta40 ratio up-regulates CRABP1, which in turn reduces the differentiation potential of the human neuroblastoma cell line SH-SY5Y, but increases cell proliferation. This work might contribute to the better understanding of AD neurogenesis, currently a controversial topic.

Grimm MO, Grimm HS, Tomic I, Beyreuther K, Hartmann T, Bergmann C. · Department of Neurology, Saarland University, Kirrbergerstrasse, 66421 Homburg/Saar, Germany. · J Biol Chem. · Pubmed #18308724 links to  free full text

Abstract: The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide Abeta(42). In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and Abeta generation. However, the cellular mechanism of lipid-dependent Abeta production remains unclear. Here we describe that the two enzymatic activities responsible for Abeta production, beta-secretase and gamma-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the beta-secretase beta-site amyloid precursor protein cleaving enzyme and the presenilin-containing gamma-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.

Schneider A, Schulz-Schaeffer W, Hartmann T, Schulz JB, Simons M. · Center for Biochemistry and Molecular Cell Biology, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. · Neurobiol Dis. · Pubmed #16777421 No free full text.

Abstract: A key event in the pathogenesis of Alzheimer's disease is the conversion of soluble amyloid Abeta-peptide into toxic aggregates. Here, we studied the effect of cholesterol depletion on the formation of insoluble Abeta. We found that reduction of neuronal cholesterol by approximately 25% reduced the neuronal formation of insoluble Abeta without affecting the secretion of soluble Abeta. Moreover, we demonstrate that Abeta-oligomers from Alzheimer's disease brains associate with a detergent-resistant membrane fraction in a cholesterol-dependent manner. These results suggest a key role for cholesterol in aggregation of Abeta.

Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lütjohann D, Hartmann T, Tanila H. · Department of Neuroscience and Neurology, University of Kuopio, Finland. · Neurobiol Dis. · Pubmed #16765602 No free full text.

Abstract: The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptide (Abeta) in the brain. Seven experimental diets with varying n-6/n-3-ratio, saturated and polyunsaturated fatty acid and cholesterol contents were fed to transgenic APPswe/PS1dE9 mice for 3-4 months beginning at a young adult age (6 months). Hippocampal Abeta levels were determined with ELISA and plaque load by using immunocytochemistry. A typical Western diet with 40% saturated fatty acids and 1% of cholesterol increased, while diets supplemented with docosahexaenoic acid (DHA) decreased Abeta levels compared to regular (soy oil based) diet. DHA diet also decreased the number of activated microglia in hippocampus and increased exploratory activity of transgenic mice, but did not improve their spatial learning in the water maze. The favorable effect of DHA on Abeta production was verified in two different cell lines. Regulation of dietary lipid intake may offer a new tool to reduce the risk of Alzheimer's disease at the population level.

Duering M, Grimm MO, Grimm HS, Schröder J, Hartmann T. · Center for Molecular Biology Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. · Neurobiol Aging. · Pubmed #15718035 No free full text.

Abstract: More than 130 known mutations in the presenilin-1 (PS1) gene result in familial Alzheimer's disease (FAD) with a mutation specific age of disease onset. These mutations increase amyloid beta 42 (A beta42) levels, and this increase has been validated in recent years as one pathogenic factor in FAD. However, further malfunctions of mutant presenilin-1 are discussed as well. In order to assess the weight of A beta42 regarding the pathogenesis of FAD, we expressed mutant forms of PS1 (30-65 years onset age) in COS-7 cells and analyzed amyloid beta levels by a novel ELISA. We found a strong correlation (r = 0.98; p<0.001) between the A beta40/42-ratio and mean age of disease onset indicating a substantial extent of A beta42 contribution to FAD pathology. Our data strongly suggest that A beta42 is the decisive factor for age of onset in FAD.

Fassbender K, Walter S, Kühl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K. · Department of Neurology, University of Goettingen, 37075 Goettingen, FRG. · FASEB J. · Pubmed #14597556 links to  free full text

Abstract: To rapidly respond to invading microorganisms, humans call on their innate immune system. This occurs by microbe-detecting receptors, such as CD14, that activate immune cells to eliminate the pathogens. Here, we link the lipopolysaccharide receptor CD14 with Alzheimer's disease, a severe neurodegenerative disease resulting in dementia. We demonstrate that this key innate immunity receptor interacts with fibrils of Alzheimer amyloid peptide. Neutralization with antibodies against CD14 and genetic deficiency for this receptor significantly reduced amyloid peptide induced microglial activation and microglial toxicity. The observation of strongly enhanced microglial expression of the LPS receptor in brains of animal models of Alzheimer's disease indicates a clinical relevance of these findings. These data suggest that CD14 may significantly contribute to the overall neuroinflammatory response to amyloid peptide, highlighting the possibility that the enormous progress currently being made in the field of innate immunity could be extended to research on Alzheimer's disease.

Schönknecht P, Pantel J, Hartmann T, Werle E, Volkmann M, Essig M, Amann M, Zanabili N, Bardenheuer H, Hunt A, Schröder J. · Department of Psychiatry, Section of Geriatric Psychiatry, University of Heidelberg, Voss-Street 4, Heidelberg D-69115, Germany. · Psychiatry Res. · Pubmed #14561434 No free full text.

Abstract: Increased tau levels are a well-established finding in Alzheimer's disease (AD). In contrast, the potential value of tau levels in the differential diagnosis of AD, vascular dementia (VD) and major depression warrants further investigation. The potential impact of psychotropic medication also needs to be established. We investigated cerebrospinal fluid (CSF) tau protein concentrations in 88 patients with AD, 23 patients with VD, 25 patients with major depression and 17 age-paralleled controls without cognitive impairment with respect to important clinical variables, type and dosage of psychotropic medication and cerebral changes as assessed by magnetic resonance imaging (MRI). The AD patients showed significantly elevated tau levels compared with patients with VD or major depression and controls. Tau levels obtained in the VD group were intermediate, with significant differences from both AD patients and patients with major depression and controls. Within the AD group, no significant correlation between tau levels, severity of dementia, age, duration of disease, type and dosage of psychotropic medication or MRI volumetric changes arose. A subgroup of AD patients without increased tau levels was characterized by a significantly larger percentage of patients with presenile onset.

Gamliel A, Teicher C, Hartmann T, Beyreuther K, Stein R. · Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Israel. · Neuroscience. · Pubmed #12605888 No free full text.

Abstract: Programmed cell death, or apoptosis, has been implicated in Alzheimer's disease. Mutations in the presenilin (PS) genes, PS1 and PS2, are a major cause of early-onset familial Alzheimer's disease (FAD). Previous studies have suggested that the PS play a role in apoptosis. However, the mechanisms whereby presenilins affect apoptosis and the relationship of FAD-associated presenilin mutants to the apoptotic effect have not been elucidated. In the present study, in an attempt to further explore the effect of PS2 on apoptosis we examined whether overexpression of wild-type or mutant PS2 can directly induce apoptosis or increase cell susceptibility to apoptosis in various cell lines, such as N2a, CHO, and HEK 293T. Wild-type or mutant PS2 was transiently transfected into these cell lines and the viability of the transfected cells was evaluated by their morphology, DNA fragmentation and condensation, appearance of sub-G(1/0) cells, and caspase activation. We also examined the susceptibility of the PS2-transfected cells to apoptosis induced by the apoptotic inducers staurosporine and H(2)O(2). Our results showed that overexpression of either wild type or mutant PS2 in these cell lines did not directly induce apoptosis or increase the susceptibility to apoptosis induced by staurosporine or H(2)O(2). Taken together, these results suggest that overexpression of PS2 does not cause pro-apoptotic effects, at least not in the cellular systems and conditions employed in this study, and therefore it seems unlikely that apoptosis plays a prominent role in the neuropathological effects of PS2 in Alzheimer's disease.

Schönknecht P, Lütjohann D, Pantel J, Bardenheuer H, Hartmann T, von Bergmann K, Beyreuther K, Schröder J. · Section of Geriatric Psychiatry, Department of Psychiatry, University of Heidelberg, Voss-Strasse 4, 69115, Germany. · Neurosci Lett. · Pubmed #11983301 No free full text.

Abstract: Experiments in cell cultures indicate that accumulation of cholesterol in hippocampal neurons results in an accelerated cleavage of amyloid precursor protein into amyloidogenic components. To be eliminated from the brain, cholesterol is converted to 24S-hydroxycholesterol which may reflect cerebral cholesterol turnover. We investigated cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol in a group of 14 Alzheimer's disease (AD) patients and ten healthy controls without any cognitive deficits or psychiatric or neurological disorders. To exclude potential effects of circulating plasma cholesterol on CSF 24S-hydroxycholesterol levels, only patients and controls with cholesterol levels in the normal range of 150-230 mg/dl were included. We found significantly elevated 24S-hydroxycholesterol CSF but not plasma levels in AD patients compared with healthy controls. Our results demonstrate that CSF 24S-hydroxycholesterol is increased in AD. This effect does not seem to be triggered by plasma cholesterol levels since the latter did not significantly differ between groups.

Gamliel A, Teicher C, Michaelson DM, Pradier L, Hartmann T, Beyreuther K, Stein R. · Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv, 69978, Israel. · Mol Cell Neurosci. · Pubmed #11817902 No free full text.

Abstract: Mutations in the presenilin genes PS1 and PS2 are a major cause of early onset familial Alzheimer's disease (AD). Previous studies have suggested that presenilins have several functions, including gamma-secretase activity. It was also shown that presenilin expression is increased in the brains of some AD patients and ischemic rodents. The present study examines the effect of increased presenilin expression on protein synthesis. We show here that overexpression of wild-type PS2 (PS2wt) or PS2 mutant containing the FAD mutation N141I (PS2mut) in various cell lines inhibits the synthesis of coexpressed reporter and endogenous proteins. Furthermore, endogenous PS2 seems to be needed for translation inhibition since PS2 null fibroblasts were translationally more active than PS2(+/+) fibroblasts under conditions known to inhibit translation. Overexpression of PS1 also appeared to cause inhibition of protein synthesis, but its effect was much weaker than that of PS2. Taken together, the results suggest that increased expression of PS2 and possibly also of PS1 inhibits translation and that presenilins may function as regulators of protein synthesis.

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.

Schönknecht P, Pantel J, Klinga K, Jensen M, Hartmann T, Salbach B, Schröder J. · Section of Geriatric Psychiatry, Department of Psychiatry, University of Heidelberg, Voss-Strasse 4, D-69115, Heidelberg, Germany. · Neurosci Lett. · Pubmed #11427315 No free full text.

Abstract: Recent in-vitro studies indicate that estrogens such as 17beta-estradiol (E2) may decrease the production of beta-amyloid 1-42 (Abeta42), a peptide central for the formation of senile plaques in Alzheimer's disease (AD). To test this hypothesis in a clinical study, cerebrospinal fluid levels of E2 were compared between 30 female AD patients and 11 female patients with non-dementing diseases such as major depression and investigated with respect to beta-amyloid 1-40 and Abeta42 levels. E2 levels were significantly (P<0.05) lower in the AD group than in controls; within the AD group E2 levels were inversely correlated with Abeta42 concentrations (r=-0.36, P=0.05). This is the first clinical study providing evidence for an influence of E2 on Abeta42 metabolism in vivo. This observation corresponds to the putative beneficial effects of estrogen replacement therapy on the development and course of AD.

Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. · Department of Neurology, Clinic Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. · Proc Natl Acad Sci U S A. · Pubmed #11296263 links to  free full text

Abstract: Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated Abeta42 levels and the varepsilon4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Abeta42 and Abeta40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Abeta42 and Abeta40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of Abeta42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.

Jensen M, Hartmann T, Engvall B, Wang R, Uljon SN, Sennvik K, Näslund J, Muehlhauser F, Nordstedt C, Beyreuther K, Lannfelt L. · Karolinska Institutet, NEUROTEC Department, Huddinge, Sweden. · Mol Med. · Pubmed #10949910 links to  free full text

Abstract: BACKGROUND: The amyloid beta (Abeta) peptide is a key molecule in the pathogenesis of Alzheimer's disease. Reliable methods to detect and quantify soluble forms of this peptide in human biological fluids and in model systems, such as cell cultures and transgenic animals, are of great importance for further understanding the disease mechanisms. In this study, the application of new and highly specific ELISA systems for quantification of Abeta40 and Abeta42 (Abeta peptides ending at residues 40 or 42, respectively) in human cerebrospinal fluid (CSF) are presented. MATERIALS AND METHODS: Monoclonal antibodies WO-2, G2-10 and G2-11 were thoroughly characterized by (SPOT) epitope mapping and immunoprecipitation/mass spectrometry. We determined whether aggregation affected the binding capacities of the antibodies to synthetic peptides and whether components of the CSF affected the ability of the antibodies to bind synthetic Abeta1-40 and Abeta1-42 peptides. The stability of Abeta40 and Abeta42 in CSF during different temperature conditions was also studied to optimize sample handling from lumbar puncture to Abeta assay. RESULTS: The detection range for the ELISAs were 20-250 pM. The intra-assay variations were 2% and 3%, and the inter-assay variations were 2% and 10% for Abeta40 and Abeta42, respectively. The antibodies specifically detected the expected peptides with equal affinity for soluble and fibrillar forms of the peptide. The presence of CSF obstructed the recognition of synthetic peptides by the antibodies and the immunoreactivity of endogenous CSF Abeta decreased with increasing storage time and temperature. CONCLUSIONS: This study describes highly sensitive ELISAs with thoroughly characterized antibodies for quantification of Abeta40 and Abeta42, an important tool for the understanding of the pathogenesis of Alzheimer's disease. Our results pinpoint some of the difficulties associated with Abeta quantification and emphasize the importance of using a well-documented assay.