Alzheimer Disease: Delacourte A

Delacourte A. · Inserm Unit 837-JPARC, Lille cedex, France. · J Alzheimers Dis. · Pubmed #18688095 No free full text.

Abstract: Most dementing disorders result from a degenerating process named tauopathy. Alzheimer disease is the most frequent one, but only one among the large spectrum of tau-related diseases. Cognitive impairment is related, first of all, to the neocortical location of this degenerating process. However, the nature and the mechanisms leading to tauopathy can be very different. This is demonstrated by familial mutations on the tau gene as well as by the different morphological and biochemical patterns of tau lesions. Therefore there is no doubt that tau is an etiological agent. But the persistent and unsolved question is the basic mechanism leading to neurodegeneration: is it due to the toxic effect of aggregated tau, or a loss of tau function, or both? Some answers may come from a more focused interest towards sporadic tauopathies. Most of them are characterized by a degenerating process starting in a specific and vulnerable brain area and consuming the connected neuronal network, like a chain reaction. In other words, sporadic tauopathies are mostly a destabilization of specific neuronal networks that should be modeled for an efficient therapeutic approach.

Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin ML, Grognet P, Bombois S, Blum D, Delacourte A, Pasquier F, Vanmechelen E, Schraen-Maschke S, Buée L. · Inserm, U837, place de Verdun, 59045 Lille, France. · Expert Rev Proteomics. · Pubmed #18466052 No free full text.

Abstract: Microtubule-associated Tau proteins belong to a family of factors that polymerize tubulin dimers and stabilize microtubules. Tau is strongly expressed in neurons, localized in the axon and is essential for neuronal plasticity and network. From the very beginning of Tau discovery, proteomics methods have been essential to the knowledge of Tau biochemistry and biology. In this review, we have summarized the main contributions of several proteomic methods in the understanding of Tau, including expression, post-translational modifications and structure, in both physiological and pathophysiological aspects. Finally, recent advances in proteomics technology are essential to develop further therapeutic targets and early predictive and discriminative diagnostic assays for Alzheimer's disease and related disorders.

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Buée L, Delacourte A. · Inserm U 815, Centre Jean-Pierre Aubert, Institut de médecine prédictive et recherche thérapeutique, Lille. · Psychol Neuropsychiatr Vieil. · Pubmed #17194646 No free full text.

Abstract: Neurofibrillary degeneration is well correlated to the clinical signs of Alzheimer disease. However, the amyloid cascade is so well established in the scientific and medical community that the role of neurofibrillary degeneration in Alzheimer's disease etiopathogenesis is often underestimated. However, neuronal vulnerability is clearly a key factor for facilitating the amyloid pathology which allows the propagation of the degenerating process. In the present work, the role of tau pathology as both diagnostic marker and therapeutic target is highlighted in Alzheimer disease and related disorders.

Delacourte A. · Unité Inserm 815, Lille, France. · Rev Neurol (Paris). · Pubmed #17028557 No free full text.

Abstract: The natural and molecular history of familial or sporadic Alzheimer's disease (AD) shows that APP (amyloid protein precursor) dysfunction is a consensual central etiological factor in Alzheimer's disease (AD). This is demonstrated by 1) genetic defects involving APP gene or APP dysfunction (such as PS1 or PS2), leading to the formation of neocortical amyloid plaques in familial AD; 2) transgenic mice with these mutated genes that develop plaques; 3) both sporadic and familial AD develop plaques. But two alternatives to explain the physiopathology can be proposed: a gain of toxic function of AB peptide (reflected by the amyloid cascade hypothesis) or a loss of function of APP, a ubiquitous and well conserved protein with numerous possible neurotrophic activities. On the other hand, AD is also characterized by another inescapable degenerating process: tauopathy, an intraneuronal aggregation of tau proteins into neurofibrillary tangles. Remarkably enough, progression of tauopathy in neocortical areas fully explains the progressive clinical deficits of AD, from memory loss to aphasia, apraxia, agnosia. Also one has to bare in mind that most demented patients and most dementing neurodegenerative disorders have a tauopathy. From that, it is concluded that APP an Tau are solid therapeutic targets. But if we know that APP and Tau dysfunctions interact to boost neurodegeneration in AD, we still do no know what are the intraneuronal signaling pathways to activate or to inhibit to stop the degenerating process. There are many hypotheses and many possible approaches: the inhibition of toxicity of plaque, of AB protofibrils, or of AB oligomers inside or outside the neuron, using vaccination or ligands (Alzhemed). On the other hand, modulation of secretases that cleave APP by inhibiting those involved in the amyloidogenic pathway or by stimulating those of the non-amyloidogenic pathway, is a major route of research. Also modulation of kinases or phosphatases possibly involved in the aggregation of tau is also investigated. Because animal models are not perfectly relevant, at the end of the long and costly pathway of drug discovery, therapeutic trials are the only way to test these different hypotheses.

Delacourte A, Buée L. · Unité Inserm 422, Lille. · Psychol Neuropsychiatr Vieil. · Pubmed #16316817 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that affects people slowly, insidiously, progressively but irreversibly. This disease will destroy, little by little, the neurons of the hippocampal formation that sustain episodic memory, and the neurons of the polymodal association areas involved in all other cognitive functions. AD is characterized by two types of brain lesions: amyloid plaques and neurofibrillary degeneration. Three major molecular actors are involved in the dynamic of neurodegeneration, but the precise role of each is still a matter of debate: the first one is APP (amyloid protein precursor) that is cleaved to release Abeta peptide that will aggregate into plaques. The last one is the microtubule-associated protein tau that assembles into paired helical filaments in neurons to constitute neurofibrillary degeneration. The main difficulty to study AD results from the fact that this disease is specific to humans and, therefore, that there is no relevant animal model at our disposal. Transgenic mice merely reflect partial aspects of the physiopathological process, impeding therapeutic approaches such as relevant drug tests on animals. But research is in progress...

Sergeant N, Delacourte A, Buée L. · INSERM U422, 1, Place de Verdun, 59045 Lille cedex, France. · Biochim Biophys Acta. · Pubmed #15615637 No free full text.

Abstract: Microtubule-associated Tau proteins are the basic component of intraneuronal and glial inclusions observed in many neurological disorders, the so-called tauopathies. Many etiological factors, phosphorylation, splicing, and mutations, relate Tau proteins to neurodegeneration. Molecular analysis has revealed that hyperphosphorylation and abnormal phosphorylation might be one of the important events in the process leading to tau intracellular aggregation. Specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution, could characterize five main classes of tauopathies. A direct correlation has been established between the regional brain distribution of tau pathology and clinical symptoms; for instance progressive involvement of neocortical areas is well correlated to the severity of dementia in Alzheimer's disease, overall suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. Recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Overall, a better knowledge of the etiological factors responsible for the aggregation of tau proteins in brain diseases is essential for development of future differential diagnosis and therapeutic strategies. They would hopefully find their application against Alzheimer's disease but also in all neurological disorders for which a dysfunction of Tau biology has been identified.

Delacourte A, Sergeant N, Buée L. · INSERM U422, Institut de Médecine Prédictive et Recherche Thérapeutique, Place de Verdun, 59045 Lille, France. · Exp Gerontol. · Pubmed #14698810 No free full text.

Abstract: Aging is the major risk factor for numerous brain diseases. This is especially true for Alzheimer's disease (AD), a peculiar neurodegenerative disorder in that it results from the synergy of two simultaneous but distinct degenerating processes: A beta and tau pathologies. For AD, and for most neurodegenerative disorders, aggregation of full length or truncated proteins, in neurons or glial cells, or in the parenchyma, is central, but still a mystery. In addition, the late onset of these pathologies links them to ageing processes. Cause or consequence? Experimental models, that allow us to dissect these pathophysiological defects, are presented.

Hamdane M, Delobel P, Sambo AV, Smet C, Bégard S, Violleau A, Landrieu I, Delacourte A, Lippens G, Flament S, Buée L. · INSERM U422, Institut de Médecine Prédictive et Recherche Thérapeutique, Place de Verdun, F-59045 Lille Cedex, France. · Biochem Pharmacol. · Pubmed #14555242 No free full text.

Abstract: Neuronal death is a process which may be either physiological or pathological. Apoptosis and necrosis are two of these processes which are particularly studied. However, in neurodegenerative disorders, some neurons escape to these types of death and "agonize" in a process referred to as neurofibrillary degeneration. Neurofibrillary degeneration is characterized by the intraneuronal aggregation of abnormally phosphorylated microtubule-associated Tau proteins. A number of studies have reported a reactivation of the cell cycle in the neurofibrillary degeneration process. This reactivation of the cell cycle is reminiscent of the initiation of apoptosis in post-mitotic cells where G1/S markers including cyclin D1 and cdk4/6, are commonly found. However, in neurons exhibiting neurofibrillary degeneration, both G1/S and G2/M markers are found suggesting that they do not follow the classical apoptosis and an aberrant cell cycle occurs. This aberrant response leading to neurofibrillary degeneration may be triggered by the sequential combination of three partners: the complex Cdk5/p25 induces both apoptosis and the "abnormal mitotic Tau phosphorylation". These mitotic epitopes may allow for the nuclear depletion of Pin1. This latter may be responsible for escaping classical apoptosis in a subset of neurons. Since neurofibrillary degeneration is likely to be a third way to die, molecular mechanisms leading to changes in Tau phosphorylation including activation of kinases such as cdk5 or other regulators such as Pin1 could be important drug targets as they are possibly involved in early stages of neurodegeneration.

Delacourte A, Sergeant N, Wattez A, Maurage CA, Lebert F, Pasquier F, David JP. · Unité Inserm 422, 1, Place de Verdun, 59045 Lille cedex, France. · Exp Gerontol. · Pubmed #12470843 No free full text.

Abstract: Tauopathy is a concept to describe different genetic or metabolic dysfunctions of tau proteins that generate most of the known dementing disorders. Tauopathy is a degenerating process that also affects the entorhinal formation, and then the hippocampal formation in ageing. In Alzheimer's disease (AD), a disease due to APP dysfunction, a similar tauopathy process in observed in neocortical areas, well correlated to cognitive impairment. One important gap of knowledge is the relationship between tauopathy in the hippocampal formation, ageing, AD, and cognitive impairment. Here we show that the multidisciplinary analysis of numerous brains from non-demented and demented patients suggests the following observations: tauopathy of the hippocampal formation in humans is age-related but not an age-dependent process, also independent of AD, but amplified by APP dysfunctions. Tauopathy in the entorhinal and hippocampal formation could be another type of pathological dysfunction of tau proteins, and a therapeutic target to delay AD. Relevant animal models are desperately needed to address this issue.

Buée L, Hamdane M, Delobel P, Sambo AV, Bégard S, Ghestem A, Sergeant N, Delacourte A. · INSERM U422, Place de Verdun, F-59045 Lille, France. · J Soc Biol. · Pubmed #12134624 No free full text.

Abstract: Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, the recent discovery of tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 has reinforced the direct role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Conversely, recent data in myotonic dystrophy has demonstrated that indirect effect (CTG repeat expansion) leading to variations in tau alternative splicing also produce neurofibrillary degeneration.

Delacourte A. · Inserm U422, Lille. · Adv Exp Med Biol. · Pubmed #11403165 No free full text.

This publication has no abstract.

Delacourte A, Buée L. · Unit Inserm 422, 59045 Lille cedex, France. · Curr Opin Neurol. · Pubmed #10970052 No free full text.

Abstract: Tau is not only a basic component of neurofibrillary degeneration, but is also an aetiological factor, as demonstrated by mutations on the tau gene responsible for frontotemporal dementias with parkinsonism linked to chromosome 17. Polymorphisms on the tau gene and the hierarchical invasion of neocortical areas by tau pathology in numerous sporadic neurodegenerative diseases also suggest that tau pathology is a primary pathogenic event in non-familial dementing diseases and a lead for solid diagnostic and therapeutic approaches.

Delacourte A. · Inserm U. 422, 59045 Lille cedex. · Ann Biol Clin (Paris). · Pubmed #10846240 links to  free full text

This publication has no abstract.

Buée L, Delacourte A. · INSERM U422, F-59045 Lille, France. · Brain Pathol. · Pubmed #10517507 No free full text.

Abstract: Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.

Delacourte A. · Unité INSERM 422, Lille, France. · Dement Geriatr Cogn Disord. · Pubmed #10436346 No free full text.

Abstract: Neurofibrillary degeneration (NFD) is a degenerating process characterized by the intraneuronal aggregation of abnormal tau proteins. These proteins have a biochemical signature which is disease-specific. They also have a neocortical distribution which is typical of the disease. Pathological tau proteins have been analyzed qualitatively and quantitatively in all diseases that may present the clinical symptoms of frontotemporal dementias. In Alzheimer's disease, a disease with sometimes a frontal predominance, paired helical filaments (PHF) of neurofibrillary tangles are made of hyperphosphorylated tau, named PHF-tau. Their electrophoretic profile consists of four main bands (tau 55, 64, 69, 74 kD), resulting from the presence of the six tau isoforms. In Pick's disease the phosphorylated tau from Pick bodies are made of two major components (tau 55, 64 kD) and a minor 69 kD resulting from the lack of tau isoforms with the translated exon 10 (E10-). Corticobasal degeneration (CBD) also has a different pattern of tau variants, with tau 64, 69 components and a minor tau 74. Pathological tau proteins that aggregate in CBD (and progressive supranuclear palsy) are exclusively made of E10+ tau isoforms. In frontotemporal dementias non-Alzheimer, non-Pick (Lund and Manchester criteria), we did not observe the presence of pathological tau proteins in 2 cases, but a third one presented a particular pattern of tau, with soluble pathological tau in frontotemporal areas. These data show that this group could be heterogeneous.In conclusion, the biochemical signature of tau distinguishes four classes of frontotemporal dementia. The characteristic tau phenotypes observed are linked to the specific neuronal networks that are affected in each disease.

Funalot B, Ouimet T, Claperon A, Fallet C, Delacourte A, Epelbaum J, Subkowski T, Léonard N, Codron V, David JP, Amouyel P, Schwartz JC, Helbecque N. · Institut National de la Santé et de la Recherche Médicale Unit 573, 75014 Paris, France. · Mol Psychiatry. · Pubmed #15340356 No free full text.

Abstract: Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.

Rudinskiy N, Grishchuk Y, Vaslin A, Puyal J, Delacourte A, Hirling H, Clarke PG, Luthi-Carter R. · Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Station 15, Lausanne CH1015, Switzerland. · J Biol Chem. · Pubmed #19240038 No free full text.

Abstract: Clathrin-dependent endocytosis is mediated by a tightly regulated network of molecular interactions that provides essential protein-protein and protein-lipid binding activities. Here we report the hydrolysis of the alpha- and beta2-subunits of the tetrameric adaptor protein complex 2 by calpain. Calcium-dependent alpha- and beta2-adaptin hydrolysis was observed in several rat tissues, including brain and primary neuronal cultures. Neuronal alpha- and beta2-adaptin cleavage was inducible by glutamate stimulation and was accompanied by the decreased endocytosis of transferrin. Heterologous expression of truncated forms of the beta2-adaptin subunit significantly decreased the membrane recruitment of clathrin and inhibited clathrin-mediated receptor endocytosis. Moreover, the presence of truncated beta2-adaptin sensitized neurons to glutamate receptor-mediated excitotoxicity. Proteolysis of alpha- and beta2-adaptins, as well as the accessory clathrin adaptors epsin 1, adaptor protein 180, and the clathrin assembly lymphoid myeloid leukemia protein, was detected in brain tissues after experimentally induced ischemia and in cases of human Alzheimer disease. The present study further clarifies the central role of calpain in regulating clathrin-dependent endocytosis and provides evidence for a novel mechanism through which calpain activation may promote neurodegeneration: the sensitization of cells to glutamate-mediated excitotoxicity via the decreased internalization of surface receptors.

Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B. · Center for Human Genetics, Katholieke Universiteit Leuven and Department of Molecular and Developmental Genetics, VIB, Herestraat 49 bus 602, B-3000 Leuven, Belgium. · Proc Natl Acad Sci U S A. · Pubmed #18434550 links to  free full text

Abstract: Although the role of APP and PSEN genes in genetic Alzheimer's disease (AD) cases is well established, fairly little is known about the molecular mechanisms affecting Abeta generation in sporadic AD. Deficiency in Abeta clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/beta-secretase may also be associated with the disease. We therefore investigated changes in microRNA (miRNA) expression profiles of sporadic AD patients and found that several miRNAs potentially involved in the regulation of APP and BACE1 expression appeared to be decreased in diseased brain. We show here that miR-29a, -29b-1, and -9 can regulate BACE1 expression in vitro. The miR-29a/b-1 cluster was significantly (and AD-dementia-specific) decreased in AD patients displaying abnormally high BACE1 protein. Similar correlations between expression of this cluster and BACE1 were found during brain development and in primary neuronal cultures. Finally, we provide evidence for a potential causal relationship between miR-29a/b-1 expression and Abeta generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and Abeta levels in sporadic AD.

Boutillier S, Lannes B, Buée L, Delacourte A, Rouaux C, Mohr M, Bellocq JP, Sellal F, Larmet Y, Boutillier AL, Loeffler JP. · Inserm, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France. · Neurodegener Dis. · Pubmed #17934324 No free full text.

Abstract: BACKGROUND/AIMS: Alzheimer's disease (AD) is characterized by extracellular Abeta peptide deposition originating from amyloid precursor protein cleavage and intracellular neurofibrillary tangles resulting from pathological tau protein aggregation. These processes are accompanied by dramatic neuronal losses, further leading to different cognitive impairments. Neuronal death signalings involve gene expression modifications that rely on transcription factor alterations. Herein, we investigated the fate of the Sp family of transcription factors in postmortem brains from patients with AD disease and in different contexts of neuronal death. METHODS/RESULTS: By immunohistochemistry we found that the Sp3 and Sp4 levels were dramatically increased and associated with neurofibrillary tangles and pathological tau presence in neurons from the CA1 region of the hippocampus, as well as the entorhinal cortex of AD patient brains. The Sp transcription factor expression levels were further analyzed in cortical neurons in which death is induced by amyloid precursor protein signaling targeting. While the Sp1 levels remained constant, the Sp4 levels were slightly upregulated in response to the death signal. The Sp3 isoforms were rather degraded. Interestingly, when overexpressed by transfection experiments, the three Sp family members induced neuronal apoptosis, Sp3 and Sp4 being the most potent proapoptotic factors over Sp1. CONCLUSION: Our data evidence Sp3 and Sp4 as new hallmarks of AD in postmortem human brains and further point out that Sp proteins are potential triggers of neuronal death signaling cascades.

Cacquevel M, Launay S, Castel H, Benchenane K, Chéenne S, Buée L, Moons L, Delacourte A, Carmeliet P, Vivien D. · INSERM, INSERM-Avenir, tPA in the working brain, Caen, France. · Neurobiol Dis. · Pubmed #17566751 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder in the ageing population. It is characterized by the cerebral accumulation of toxic amyloid-beta peptide assemblies (Abeta). The serine protease plasmin, which is generated from the inactive zymogen plasminogen through its proteolytic cleavage by tissue- (tPA) or urokinase-type plasminogen activator, has been implicated in the catabolism of Abeta peptides. In this report, we studied the regulation of tPA activity in vivo during ageing in normal mice and in a mouse model of AD characterized by an exacerbated endogenous Abeta accumulation. We observed that cerebral tPA activity was decreased during ageing in normal mice and that this effect was worsened in mice overproducing Abeta peptides. These phenomena result, respectively, from a decrease in tPA expression and from an increase in the production of one of the tPA inhibitors, the plasminogen activator inhibitor type 1 (PAI-1). A similar study in sporadic AD and age-matched control brain tissues revealed that the tPA proteolytic activity was negatively correlated to Abeta peptides levels supporting the data observed in mice. Altogether, our data support a model in which amyloid deposition induces a decrease in tPA activity through the overproduction of PAI-1 by activated glial cells.

Kashani A, Lepicard E, Poirel O, Videau C, David JP, Fallet-Bianco C, Simon A, Delacourte A, Giros B, Epelbaum J, Betancur C, El Mestikawy S. · INSERM, U513, 94000 Créteil, France. · Neurobiol Aging. · Pubmed #17531353 No free full text.

Abstract: Several lines of evidence suggest that the glutamatergic system is severely impaired in Alzheimer disease (AD). Here, we assessed the status of glutamatergic terminals in AD using the first available specific markers, the vesicular glutamate transporters VGLUT1 and VGLUT2. We quantified VGLUT1 and VGLUT2 in the prefrontal dorsolateral cortex (Brodmann area 9) of controls and AD patients using specific antiserums. A dramatic decrease in VGLUT1 and VGLUT2 was observed in AD using Western blot. Similar decreases were observed in an independent group of subjects using immunoautoradiography. The VGLUT1 reduction was highly correlated with the degree of cognitive impairment, assessed with the clinical dementia rating (CDR) score. A significant albeit weaker correlation was also observed with VGLUT2. These findings provide evidence indicating that glutamatergic systems are severely impaired in the A9 region of AD patients and that this impairment is strongly correlated with the progression of cognitive decline. Our results suggest that VGLUT1 expression in the prefrontal cortex could be used as a valuable neurochemical marker of dementia in AD.

Evans TA, Raina AK, Delacourte A, Aprelikova O, Lee HG, Zhu X, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Int J Med Sci. · Pubmed #17505559 links to  free full text

Abstract: In Alzheimer disease, neuronal degeneration and the presence of neurofibrillary tangles correlate with the severity of cognitive decline. Neurofibrillary tangles contain the antigenic profile of many cell cycle markers, reflecting a re-entry into the cell cycle by affected neurons. However, while such a cell cycle re-entry phenotype is an early and consistent feature of Alzheimer disease, the mechanisms responsible for neuronal cell cycle are unclear. In this regard, given that a dysregulated cell cycle is a characteristic of cancer, we speculated that alterations in oncogenic proteins may play a role in neurodegeneration. To this end, in this study, we examined brain tissue from cases of Alzheimer disease for the presence of BRCA1, a known regulator of cell cycle, and found intense and specific localization of BRCA1 to neurofibrillary tangles, a hallmark lesion of the disease. Analysis of clinically normal aged brain tissue revealed systematically less BRCA1, and surprisingly in many cases with apparent phosphorylated tau-positive neurofibrillary tangles, BRCA1 was absent, yet BRCA1 was present in all cases of Alzheimer disease. These findings not only further define the cell cycle reentry phenotype in Alzheimer disease but also indicate that the neurofibrillary tangles which define Alzheimer disease may have a different genesis from the neurofibrillary tangles of normal aging.

Vingtdeux V, Hamdane M, Loyens A, Gelé P, Drobeck H, Bégard S, Galas MC, Delacourte A, Beauvillain JC, Buée L, Sergeant N. · INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Lille, France. · J Biol Chem. · Pubmed #17468104 links to  free full text

Abstract: Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by gamma-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. (2007) Neurobiol. Dis. 25, 686-696). Herein, we aimed to determine the cell compartment in which AICD accumulates. We show that APP-CTFs and AICD are present in multivesicular structures. Multivesicular bodies contain intraluminal vesicles (known as exosomes) when released in the extracellular space. We demonstrate that APP, APP-CTFs, and AICD are integrated and secreted within exosomes in differentiated neuroblastoma and primary neuronal culture cells. Together with recent data showing that amyloid-beta is also found in exosomes, our data show that multivesicular bodies are essential organelles for APP metabolism and that all APP metabolites can be secreted in the extracellular space.

Bombois S, Maurage CA, Gompel M, Deramecourt V, Mackowiak-Cordoliani MA, Black RS, Lavielle R, Delacourte A, Pasquier F. · Department of Neurology, Resource and Research Memory Center, University Hospital, Lille, France. · Arch Neurol. · Pubmed #17420322 links to  free full text

Abstract: OBJECTIVE: To describe the neuropathological and biochemical findings of the brain examination of a patient enrolled in the AN-1792(QS-21) trial with an initial clinical diagnosis of Alzheimer disease (AD), in whom Lewy body variant was thereafter clinically diagnosed. DESIGN: A case report. SETTING: University memory clinic. Patient A 74-year-old woman with clinical features of probable AD. Intervention The patient received 2 injections of 225 mug of AN-1792 (beta-amyloid [Abeta]) plus 50 mug of the adjuvant QS-21 at an interval of 4 weeks. The patient was an antibody responder with an IgG anti-AN-1792 antibody titer exceeding 10 000 and an IgM titer exceeding 3500. Maximum serum anti-Abeta titers were reached in 4.7 months. During the 3 following years, while the Mini-Mental State Examination score remained globally stable despite several confusional episodes, she developed clinical features of dementia with Lewy bodies. The patient died 34 months postimmunization. An autopsy was performed. MAIN OUTCOME MEASURES: Neuropathological and biochemical examination of the brain using standardized evaluation for tau, beta-amyloid, and synuclein deposits. RESULTS: Neither neuropathological nor biochemical examinations showed amyloid deposit in the brain of this immunized patient. For tau deposition, Braak stage was IV/VI, and the Western blot analysis score was 9c/10. The neuropathological semiquantitative score for alpha-synuclein aggregation was 4. There was no inflammation. These results were compared with those of an age-matched patient with AD and a control devoid of any neurological disease. CONCLUSION: In this Lewy body variant case, with globally stable functional and cognitive features, Abeta immunization resulted in a significant clearance of amyloid deposits, with remaining tau and synuclein pathological features in the brain. Patients with a Lewy body variant of AD should not be excluded from enrollment in Abeta-immunization trials.