FOUNDATIONGRANTSEU-PROJECTSNEWS

DIADEM



Early Diagnosis of Alzheimer's Disease and Related Dementia

Contract number:
QLK3-CT-2001-02362
Duration: 1 October 2001 – 30 September 2004
Total project costs: 7,598,179 EUR | EU contribution: 3,830,276 EUR

Contractors: VERUM - Stiftung für Verhalten und Umwelt, München, Germany | Universität Zürich, Switzerland | Georg-August-Universität Göttingen, Germany | Ludwigs-Maximilians-Universität München, Germany | VIB - Vlaams Instituut voor Biotechnologie, Leuven, Belgium | Fundacion para la Investigacion Medica Aplicada, Pamplona, Spain | EleGene GmbH, Martinsried, Germany | Evotec NeuroSciences GmbH, Hamburg, Germany | Universidade de Aveiro, Portugal | Fondazione Cavalieri Ottolenghi Scientific Institute, Orbassano, Italy | National and Kapodistrian University Athens, Greece | Karolinska Institutet, Huddinge, Sweden | University College London, United Kingdom | Ruprecht-Karls-Universität Heidelberg, Germany

OBJECTIVES: The work packages of this multi-institutional research programme were designed to generate knowledge of a better understanding of the molecular mechanisms associated with the pathophysiology of Alzheimer’s disease (AD) and related dementia. Basic molecular neurobiology was integrated into a clinical research programme in a two-way orientation: Molecules identified in the basic research studies were to be tested in clinical settings for their pathophysiological relevance in the diagnosis and therapy of dementia, and clinically identified molecules with a role in genetics or as a disease marker were to be analysed in basic research study protocols for their neurobiological functions. This combined approach should make it be possible to identify novel genes and proteins associated with dementia, and to validate all candidate markers that result from the pre-clinical studies for their potential as a biomarker of dementing diseases. The combination of basic and clinical research with powerful developments in high-throughput screening and chip technology and combinatorial chemistry should lead to products that are useful in the diagnosis and treatment, and, thus, in the prevention of dementia. To achieve the goal of this integrated basic, clinical and biotechnological research programme two biotech companies with access to extensive technology have been included in the consortium. It is their task to develop a highly parallel assay device that can test simultaneously many biomarkers for dementia and drugs for disease prevention.

RESEARCH AND RESULTS: In work package “animal models” the goal was to identify mechanisms that reduce brain amyloid formation, to characterise the role of alpha-synuclein in neurodegeneration associated with dementia, to analyse the role of presenilins in neurons involved in memory, and to determine the neuronal phenotypes of expressing human neprilysin, insulin degrading enzyme, PS1, PS2, BACE-1 and alpha-synuclein in experimental animal models. To detect pathological processes at early stages of neurodegeneration, experiments were carried out to test whether the disease related genes and gene products influence the expression of known and novel disease markers by applying DNA array technology. To provide insights into the roles of these genes in intact brains, additional experiments were conducted in genetically modified mice, C. elegans and Drosophila. Among the substantial advances, these stand out: (1) Neuronal expression of neprolysin reduced amyloid brain pathology from developing in APP transgenic mice but neprolysin up-regulation did not remove amyloid plaques once they were established. (2) The transmembrane domain but not the cytoplasmic tail of nicastrin is required to form an active gamma-secretase complex. (3) C. elegans and saccharomyces yeast are powerful systems for conducting genome-wide high-throughput screens to detect drugs that interact with proteins that are relevant to aging and neurodegeneration. (4) BACE1 and BACE2 knockout mice were both normal and fertile, although there was 50% infant mortality in BACE1 mice. (5) Transgenic mice that over-expressed both alpha-synuclein and tau had age-dependent memory impairments with a 5 times increase in amyloid and neurofibrillar tangle formation and 40% increase in neuronal loss in the entorhinal cortex. (6) Drosophila that overexpress transgenic cDNAs for human BACE1 and APP display amyloid deposits in the eye and wing morphologic abnormalities that can be reversed by secretase inhibitors.

The work package “cellular pathogenesis” was to elucidate the interactions underlying the synthesis, post-translational processing, degradation, and pathological accumulation of proteins associated with neuro-degeneration and dementia using cultured cells and model organisms. Special emphasis was placed on APP proteolysis, factors that are involved in prion protein infectivity, and the links between Abeta, tau, alpha-synuclein and PrP. Another goal was to determine which of the genes/gene products can be used as disease markers and which can be targets for drug treatment. Some of the highlights are: (1) TAP or myc-tagged murine PrP rescued the lethality in mice expressing n-terminally truncated PrP. (2) Lithium treatment decreased Abeta peptide secretion from primary chicken neuronal cells but specifically increased intracellular Abeta1-38. (3) There are six individual proteolytically active gamma-secretase complexes. (4) The phosphory-lation state of specific amino acids in the intracellular domain of APP is crucial to determining APP processing and metabolism. (5) Lowering cholesterol in membrane lipid rafts increases APP beta cleavage, implying that treatment to decrease cholesterol may actually worsen AD by increasing amyloid production. A few goals had to be dropped due to insurmountable technical problems, such as low sensitivity of the microtiter format binding Abeta assay based on PrPB binding. Another few remained incomplete due to their challenging complexity.

The work package “biological and genetic markers” was to identify and characterise genetic and protein markers for the early and differential diagnosis of dementias. New candidate markers were screened in samples of DNA, serum and CSF from well documented cases of AD and related dementias collected from collaborating centres specialising in the diagnosis and clinical care of dementia. Genetic risk factors were identified by genome-wide screening, linkage and association methods. Candidate protein markers were assayed in body fluids of patients in order to determine diagnostic sensitivity and specificity. In many instances, state-of-the-art neuroimaging data were generated to complement the clinical information. Genetic analyses were carried out: a case-control association study identified five new candidate risk genes for sporadic AD, a genome-wide scan in selected AD families was started, and there is progress in understanding the pathophysiology of the arctic APP mutation. CSF candidates as diagnostic or surrogate markers were identified, and work started to optimise their measurement on quantitative high throughput technological platforms. Especially noteworthy advances include: (1) Strong collaboration among four contractors to collect new families and to store and analyse a growing number of genetic samples. (2) From an expanding set of DNA samples of histologically-confirmed patients and control subjects several cholesterol-related genes that are associated with AD have been identified. (3) Quantitative MRI volumetric measures of brain atrophy correlate highly with clinical measures of cognitive decline. (4) Active immunization with pre-aggregated synthetic Abeta42 exerts positive effects on cognition.

The detection of new candidate risk genes for developing AD by screening families with familial AD and the determination of the relation between proteins found in the biological samples and the clinical aspects of specific dementing illnesses were still in progress at the end of the project.

BENEFITS: Considering the enormous burden for society caused by AD and related dementia, the DIADEM project has a number of social, medical and economic implications. It will have a major medical impact since the findings of the DIADEM project may create the basis for a totally new approach in diagnosis and in treatment of these diseases by developing drugs which effectively arrest, prevent or reverse the progress of the illness or by replacing genes of abnormal composition, that are responsible for the breakout of the diseases, through gene therapy. It will have, too, an economic impact, since the results which led until now to the application of three patents offer a great chance to the contributing industry. Contrary to all expectations, it has proven a far more difficult goal to achieve the identification of other genes for late onset AD besides ApoE than was anticipated and to go from promising genetic linkage results to reproducible and clear genetic associations. Despite this difficulty, investigators in the DIADEM consortium conducting research on some of the most fundamental aspects of AD and related dementia were remarkably successful with their work, even if they failed to complete the development of a “DIADEM diagnostic chip”. Instead, they refined existing biochemical methods and introduced new techniques that will enable chip development in the future.

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PUBLICATIONS (team leaders in bold)

2002

Annaert W, De Strooper B (2002) A cell biological perspective on Alzheimer’s disease. Annu Rev Cell Dev Biol 18:25-51.
Eimer S, Lakowski B, Donhauser R, Baumeister R (2002) Loss of spr-5 bypasses the requirement for the C. elegans presenilin sel-12 by derepressing hop-1. EMBO J. 21(21):5787-96.

Eimer S, Donhauser R, Baumeister R (2002) The C. elegans presenilin sel-12 is required for mesodermal patterning and muscle function. Dev. Biol. 251(1):178-92.

Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM (2002) Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 8(11):1270-5.

Mohajeri MH, Saini K, Schultz JG, Wollmer MA, Hock C, Nitsch RM (2002) Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer’s disease-causing mutation. J Biol Chem 277(36):33012-7.

Mohajeri MH, Wollmer MA, Nitsch RM (2002) Abeta 42-induced increase in neprysilin is associated with prevention of amyloid plaque formation in vivo. J Biol Chem 277(38):35460-5,

2003

Dabrowski M, Aerts S, Van Hummelen P, Craessaerts K, De Moor B, Annaert W, Moreau Y, De Strooper B (2003) Gene profiling of hippocampal neuronal culture. J Neurochem 85(5):1279-88.

De Strooper B (2003) Aph-1, Pen-2, and nicastrin with presenilin generate an active alpha-secratase complex. Neuron 38(1):9-12.
Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol 5(5):486-8.

Herreman A, Van Gassen G, Dillen K, Bentahir M, Nyabi O, Craessaerts K, Mueller U, Annaert W, De Strooper B (2003) Gamma-secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. J Cell Sci 116(Pt 6):1127-36.

Hertweck M, Hoppe T, Baumeister R (2003) C. elegans, a model of aging with high-throughput capacity. Exp Gerontol 38(3):345-6.

Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38(4):547-54.

Hutter G, Heppner FL, Aguzzi A (2003) No superoxide dismutase activity of cellular prion protein in vivo. Biol Chem 384(9):1279-85.
Lakowski B, Eimer S, Gobel C, Bottcher A, Wagler B, Baumeister R (2003) Two suppressors of sel-12 encode C2H2 zinc-finger proteins that regulate presenilin transcription in Caenorhabditis elegans. Development 130(10):2117-28.

Ledesma MD, Da Silva JS, Schevchenko A, Wilm M, Dotti CG (2003) Proteomic characterisation of neuronal sphingolipid-cholesterol microdomains: role in plasminogen activation. Brain Res 987(1):107-16.

Ledesma MD, Abad-Rodriguez J, Biondi E, Navarro P, Delacourte A, Dingwall C, Dotti CG (2003) Raft disorganization leads to reduced plasmin activity in Alzheimer’s disease brains. EMBO Rep 4(12):1190-6.

Lewczuk P, Esselmann H, Meyer M, Wollscheid V, Neumann M, Otto M, Maler JM, Ruther E, Kornhuber J, Wiltfang J (2003) The amyloid-beta (Abeta) peptide pattern in cerebrospinal fluid in Alzheimer's disease: evidence of a novel carboxyterminally elongated Abeta peptide. Rapid Commun Mass Spectrom 17(12):1291-6.

Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reis K, Haass C, Saftig P, De Strooper B, Seed B (2003) The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem 278(49):48713-9.

Maddalena A, Papassotiropoulos A, Muller-Tillmanns B, Jung HH, Hegi T, Nitsch RM, Hock C (2003) Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol 60(9):1202-6.

Meier P, Genoud N, Prinz M, Maissen M, Rulicke T, Zurbriggen A, Raeber AJ, Aguzzi A (2003) Soluble dimeric prion protein binds prp(Sc) in vivo and antagonizes prion disease. Cell (1):49-60.

Nyabi O, Bentahir M, Horre K, Herreman A, Gottarid-Littell N, Van Broeckhoven C, Merchiers P, Spittaels K, Annaert W, De Strooper 0B (2003) Presenilins mutated at Asp257 or Asp385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin. J Biol Chem 278(44):43430-6.

Ostojic J, Axelman K, Lannfelt L, Froelich Fabre S (2003) No evidence of linkage to chromosome 9q21-22 in a Swedish family with frontotemporal dementia and amyotrophic lateral sclerosis. Neurosci Lett 340(3):245-7.

Prinz M, Heikenwalder M, Junt T, Schwarz P, Glatzel M, Heppner FL, Fu YX, Lipp M, Aguzzi A (2003) Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425(6961):957-62.

Prinz M, Heikenwalder M, Schwarz P, Takeda K, Akira S, Aguzzi A (2003) Prion pathogenesis in the absence of Toll-like receptor signalling. EMBO Rep 4(2):195-9.

Wiltfang J, Esselmann H, Smirnov A, Bibl M, Cepek L, Steinacker P, Mollenhauer B, Buerger K, Hampel H, Paul S, Neumann M, Maler M, Zerr I, Kornhuber J, Kretzschmar HA, Poser S, Otto M (2003) Beta-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Ann Neurol 54(2):263-7.

Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LM, Lutjohann D, Thal D, von Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A (2003) Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease. Mol Psychiatry 8(6):635-8.

2004

Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Delacourte A, Dingwall C, De Strooper B, Dotti CG (2004) Neuronal membrane cholesterol loss enhances amyloid peptide generation. J Cell Biol 167(5):953-60.

Aguzzi A, Polymenidou M (2004) Mammalian Prion Biology: One century of evolving concepts. Cell 116(2):313-27.
Amador FC, Henriques AG, da Cruz e Silva OAB, da Cruz e Silva EF (2004) Monitoring protein phosphatase 1 isoform levels as a marker for cellular stress. Neurotoxico Teratol 26(3):387-95.

Bibl M, Esselmann H, Otto M, Lewczuk P, Cepek L, Ruther E, Kornhuber J, Wiltfang J (2004) Cerebrospinal fluid amyloid beta peptide patterns in Alzheimer's disease patients and non-demented controls depend on sample pre-treatment: Indication of carrier-mediated epitope masking of amyloid beta peptides. Electrophoresis 25(17):2912-8.

Da Cruz e Silva OAB, Fardilha M, Henriques AG, Rebelo S, Guerra e Paz S, da Cruz e Silva EF (2004) Signal transduction therapeutics: a novel approach in Alzheimer’s Disease. J Mol Neurosci 23(1-2):123-42.

Greeve I, Kretzschmar D, Tschape JA, Beyn A, Brellinger C, Schweizer M, Nitsch RM, Reifegerste R (2004) Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci 24(16):3899-906.

Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S, Zinkernagel R, Aguzzi A (2004) Lymphoid follicle destruction and immunosuppression after repeated cpg oligodeoxynucleotide administration. Mat Med 10(2):187-92.

Heppner FL, Aguzzi A (2004) Recent developments in prion immunotherapy. Curr Opin Immunol 16(5):594-8.

Hertweck M, Gobel C, Baumeister R (2004) C. elegans SGK-1 is the critical component in the Akt/PKB kinase couples to control stress response and life span. Dev Cell 6(4):577-88.

Hoflich J, Berninsone P, Gobel C, Gravato-Nobre MJ, Libby BJ, Darby C, Politz SM, Hodgkin J, Hirschberg CB, Baumeister R (2004) Loss of srf-3 encoded nucleotide sugar transporter activity in Caenorhabditis elegans alters surface antigenicity and prevents bacterial adherence. J Biol Chem 279(29):30440-8.

Janssen JC, Godbolt AK, Ioannidis P, Thompson EJ, Rossor MN (2004) The prevalence of oligoclonal bands in the CSF of patients with primary neurodegenerative dementia. J Neurol 251(2):184-8.

Koller MF, Mohajeri MH, Huber M, Wollmer MA, Roth Z'graggen BV, Sandmeier E, Moritz E, Tracy J, Nitsch RM, Christen P (2004) Active immunization of mice with an Abeta-Hsp70 vaccine. Neurodegener Dis 1(1):20-8.

Lewczuk P, Esselmann H, Bibl M, Paul S, Svitek J, Miertschischk J, Meyrer R, Smirnov A, Maler JM, Klein C, Otto M, Bleich S, Sperling W, Kornhuber J, Ruther E, Wiltfang J (2004) Electrophoretic separation of amyloid beta peptides in plasma. Electrophoresis 25(20):3336-43.

Lewczuk P, Esselmann H, Bibl M, Beck G, Maler JM, Otto M, Kornhuber J, Wiltfang J (2004) Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer's disease: original data and review of the literature. J Mol Neurosci 23(1-2):115-22.

Li Y, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Lau K, Catanese J, Sninsly J, Nowotny P, Holmans P, Hardy J, Powell J, Lovestone S, Thai L, Owen M, Williams J, Goate A, Grupe A (2004) Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study. Neurosci Lett 366(3):268-71.

Li Y, Nowotny P, Holamns P, Smemo S, Kauwe JS, Hinrichs AL, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Gogic G, Chan J, Cravchik A, Ross D, Lau K, Kwik S, Chang SY, Catanese J, Sninsky J, White TJ, Hardy J, Powell J, Lovestone S, Morris JC, Thal L, Owen M, Williams J, Goate A, Grupe A (2004) Association od late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci USA 101(44):15688-93.

Maddalena A, Papassotiropoulos A, Gonzalez-Agosti C, Signorell A, Hegi T, Pasch T, Nitsch RM, Hock C (2004) Cerebrospinal fluid profile of amyloid beta peptides in patients with Alzheimer’s disease determined by protein biochip technology. Neurodegener Dis 1(4-5):231-5.

Meissner B, Boll M, Daniel H, Baumeister R (2004) Deletion of the intestinal peptide transporter affects insulin and TOR signaling in C. elegans. J Biol Chem 179(35):36739-45.

Mohajeri MH, Saini KD, Nitsch RM (2004) Transgenice BACE expression in mouse neurons accelerates amyloid plaque pathology. Neural Transm 111(3):413-25.

Mohajeri MH, Kuehnle K, Li H, Poirier R, Tracy J, Nitsch RM (2004) Anti-amyloid activity of neprilysin in plaque-bearing mouse models of Alzheimer’s disease. FEBS Lett 562(1-3):16-21.

Myers AJ, Marshall H, Holmans P, Compton D, Crook RJP, Mander AP, Nowotny P, Smemo S, Dunstan M, Jehu L, Wang JC, Hamshere M, Morris JC, Norton J, Chakraventy S, Tunstall N, Lovestone S, Petersen R, O'Donovan M, Jones L, Williams J, Owen MJ, Hardy J, Goate A (2004) Variation in the Urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD. Am J Med Genet B Neuropsychiatr Genet 124(1):29-37.

Ostojic J, Elfgren C, Passant U, Nilsson K, Gustafson L, Lannfelt L, Froelich-Fabre S (2004) The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord 17(4):298-301.

Pittman A, Myers AJ, Duckworth J, Bryden L, Hanson M, Abou-Sleiman P, Wood NW, Hardy J, Lees A, de Silva, R (2004) The structure of the tau haplotype in controls and in progressive supranuclear palsy. Hum Mol Genet 13(12):1267-74.

Polymenidou M, Heppner FL, Pellicioli EC, Urich E, Miele G, Braun N, Wopfner F, Schatzl HM, Becher B, Aguzzi A (2004) Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc Natl Acad Sci USA 101, Suppl 2:14670-6.

Tournoy J, Bossuyt X, Snellinx A, Regent M, Garmyn M, Serneels L, Saftig P, Craessaerts K, De Strooper B, Hartmann D (2004) Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum Mol Genet 13(13):1321-31.

Von Rotz RC, Kohli BM, Bosset J, Meier M, Suzuki T, Nitsch RM, Konietzko U (2004) The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J Cell Sci 177(Pt 19):4435-48.

Westmeyer GG, Willem M, Lichtenthaler SF, Lurman G, Multhaup G, Assfalg-Machleidt I, Reiss K, Saftig P, Haass C (2004) Dimerization of beta-site beta-amyloid precursor protein-cleaving enzyme. J Biol Chem 279(51):53205-12.

Special issue on the DIADEM research work with contributions from all partners (2004) Neurodegener Dis 1(4-5): 157-244.

2005

Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribe E, Dalfo E, Avila J (2005) Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. Curr Alzheimer Res 2(1):3-18.

Fotinopoulou A, Tsachaki M, Vlavaki M, Poulopoulos A, Rostangno A, Frangione B, Ghiso J, Efthimiopoulos S (2005) BRI2 interacts with amyloid precursor protein (APP) and regulates amnyloid beta (Abeta) production. J Biol Chem 280(35):30768-72.

Henriques AG, Domingues SC, Fardilha M, da Cruz e Silva EF, da Cruz e Silva OA (2005) Sodium azide and 2-deoxy-D-glucose-induced cellular stress affects phosphorylation-dependent Abeta-pp processing. J Alzheimers Dis 7(3):201-12.

Ledesma MD, Dotti CG (2005) The conflicting role of brain cholesterol in Alzheimer's disease: lessons from the brain plasminogen system. Biochem Soc Symp (72):129-38.

Medina MG, Ledesma MD, Dominguez JE, Medina M, Zafra G, Alameda F, Dotti CG, Navarro P (2005) Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. EMBO J 24(9):1706-16.

Papassotiropoulos A, Wollmer MA, Tsolaki M, Brunner F, Molyva D, Lutjohann D, Nitsch RM, Hock C (2005) A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease. J Clin Psychiatry 66(7):940-7.

Papassotiropoulos A, Tsolaki M, Wollmer MA, Molyva D, Thal DR, Huynh KD, Tracy J, Staehelin HB, Monsch AU, Nitsch RM, Hock C (2005) No association of a non-synonymous PLAU polymorphism with Alzheimer’s disease and disease-related traits. Am J Med Genet B Neuropsychiatr Genet 132(1):21-3.

Perez M, Ribe E, Rubio A, Lim F, Moran MA, Gomez-Ramos P, Ferrer I, Gomez-Isla T, Avila J (2005) Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorilation and aggregation. Neuroscience 130(2):339-47.

Ribe E, Perez M, Puig B, Lim F, Cuadrado M, Sesma T, Catena S, Sanchez B, Nieto M, Cabodevilla JF, Samaranch L, Ortiz L, Perez A, Ferrer I, Avila J, Gomez-Isla T (2005) Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 20(3):814-22.

Stenh C, Englund H, Lord A, Johansson AS, Almeida CG, Gellerfors P, Greengard P, Gouras GK, Lannfelt L, Nilsson LN (2005) Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay. Ann Neurol 58(1):147-50.

2006

Johansson AS, Berglind-Dehlin F, Karlsson G, Edwards K, Gellerfors P, Lannfelt L (2006) Physiochemical characterization of the Alzheimer's disease-related peptides Abeta1-42Arctic and Abeta1-42wt. FEBS J 273(12):2618-30.

Nieto M, Bil-Bea FJ, Dalfo E, Cuadrado M, Cabodevilla F, Sanchez B, Catena S, Sesma T, Ribe E, Ferrer I, Ramirez MJ, Gomez-Isla T (2006) Increased sensitivity to MPTP in human alpha-synuclein A20P transgenic mice. Neurobiol Aging 27(6):848-56.

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