FOUNDATIONGRANTSEU-PROJECTSDONATIONSNEWS

APOPIS



Abnormal Proteins in the Pathogenesis of Neurodegenerative Disorders

Contract number:
LSHM-CT-2003-503330
Duration: 1 January 2004 – 31 December 2006
Total project costs: about 15,100,000 EUR | EU contribution: 8,995,518 EUR

Contractors: VERUM - Stiftung für Verhalten und Umwelt, München, Germany | VIB - Vlaams Instituut voor Biotechnologie, Leuven, Belgium | Universität Zürich, Switzerland | Universität Basel, Switzerland | Eidgenössische Technische Hochschule Lausanne, Switzerland | Eidgenössische Technische Hochschule Zürich, Switzerland | Albert-Ludwigs-Universität Freiburg, Germany | Ludwig-Maximilians-Universität München, Germany | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., München, Germany | Technische Universität Darmstadt, Germany | Julius-Maximilians-Universität Würzburg, Germany | Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany | Parc Cientific de Barcelona, Spain | EMBL - European Molecular Biology Laboratory, Heidelberg, Germany | INSERM - Institut National de la Santé et de la Recherche Medicale, Paris, France | Université de Lille 2 - Droit et Santé, France | CNRS - Centre National de la Recherche Scientifique, Nice, France | National and Kapodistrian University of Athens, Greece | The Hebrew University of Israel, Jerusalem | Fondazione Cavalieri Ottolenghi, Orbassano, Italy | Università Vita-Salute San Raffaele, Milano, Italy | CEINGE Biotecnologie Avanzate Scarl, Napoli, Italy | Università degli Studi di Genova, Italy | International Institute of Molecular and Cell Biology in Warsaw, Poland | Universidade de Aveiro, Portugal | Uppsala Universitet, Sweden | Lund Universitet, Sweden | University College London, United Kingdom | University of Kent at Canterbury, United Kingdom | King's College London, United Kingdom | University of Cambridge, United Kingdom | EVOTEC Neurosciences GmbH, Hamburg, Germany | Cellzome AG, Heidelberg, Germany | Philipps-Universität Marburg, Germany

PRESENTATION AT THE END OF THE PROJECT IN DECEMBER 2006

The APOPIS project
Prof. Dr. med. Franz Adlkofer, VERUM - Stiftung für Verhalten und Umwelt, München
The APOPIS Consortium consists of 38 European research institutions experienced in the area of neuroscience. It was brought together and coordinated by the VERUM Foundation, a non-profit organisation in Munich, Germany. In line with the expectations of the EU-Commission which supported the research project together with the Swiss government with Euro 11.5 Mio the goal was several-fold, i.e. to combine the still scattered European resources, to foster the integration of high-profile European research talents, to establish synergies by co-operation and, thus, to increase European competitiveness in this area of research.
For the last three years the APOPIS Consortium attempted to get insight into the mechanisms of neuro-degeneration, to improve the clinical diagnosis of neurodegenerative disorders, and to develop prevention strategies and, eventually, effective treatment. The neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, motor neuron and prion diseases are amongst the most debilitating illnesses. This is especially true for Alzheimer which is responsible by far for most of the cases with dementia. At present, there live about 5.5 million Alzheimer patients in Europe the number of which will double every 20 years due to the constantly increasing lifespan of people, should prevention and therapy remain unaccessible. This will put an enormous strain on both social and healthcare budgets all over Europe, and in the light of the decreasing ratio of working to retired populations the financial dilemma may even become dramatic. There is currently no treatment available that can halt or prevent – let alone reverse – the resulting nerve cell degeneration, mostly due to the fact that the underlying causes of these diseases are only poorly understood.

Generation and turnover of abnormal protein aggregates
Prof. Bart de Strooper, Flanders Interuniversity Institute for Biotechnology, Leuven
Human neurodegenerative diseases are incurable disorders caused by the gradual loss of nerve cells (neurons) in the brain. Depending on the part of the brain that is affected, the disease is characterized by movement problems, like Parkinson disease, or by memory loss and ultimate dementia, like Alzheimer, Huntington and prion diseases. Microscopic analysis of post-mortem brains from patients affected by different neurodegenerative disorders revealed in each case the presence of protein aggregates, also known as 'amyloid' deposits, in specific brain regions. Proteins are the building blocks of life and as such perform different functions in the cell. Despite intense research, relatively little is known on why a harmless and functional protein, under certain pathological conditions form insoluble aggregates that deposit in the brain and cause neuronal death.
In the APOPIS Consortium we studied in detail the process of conversion of soluble proteins into insoluble aggregates and could define the basic rules that govern this crucial process. We demonstrated that the driving force for aggregation and amyloid formation is centred in a small region of the protein. Further, we developed a computer algorithm -the amyloid pattern- to identify such 'amyloidogenic' regions in disease-associated proteins. Interestingly, taking the 'amyloidogenic' region of one protein (a piece of ~6 amino acids) and fusing it to a normal protein not associated with disease is sufficient to convert it into an amyloid-prone protein that is toxic for cells. We next hypothesized that if the force driving amyloid formation is centred in a small portion of a protein, then targeting this region with small compounds might be sufficient to prevent protein aggregation and toxicity. Indeed, we demonstrated this by using compounds that we specifically designed to bind the amyloidogenic regions in individual proteins. Such anti-aggregation compounds constitute a promising novel therapy.
For the study of any human disorder it is crucial to have animal models that reproduce (some) aspects of the human disease and are therefore suitable to test the effectiveness of novel therapeutic strategies. In the Consortium we generated novel animal models that carry a human disease-associated gene and suffer from the characteristic protein aggregation and neurodegeneration. These include small animals with a short generation time (they get adult and age in few days) like the soil worm Caenorhabditis elegans and the fly Drosophila melanogaster, as well as mice that develop a disease resembling more the human condition. Promising therapies developed in the Consortium were tested in these models.

Genes and their function in neurodegenerative diseases
Prof. Christian Haass, Ludwig-Maximilians Universität, München
Most of the neurodegenerative conditions exist as sporadic and familiar forms. Whereas the cause of disease in sporadic cases is not clear, familiar cases are caused by mutations in specific genes, and therefore usually several members in a family develop the disease. Analysis of affected families led to the identification of the gene implicated, and knowing the gene has contributed to our understanding of the underlying pathogenic process. However, in most cases we know relatively little about the function of the disease-linked gene in the normal brain and on how the mutation causes the disease.
The APOPIS Consortium has greatly contributed to the identification of novel genes and gene mutations associated with neurodegenerative conditions. Just to mention one example, we identified the long-sought gene responsible for a subtype of frontotemporal dementia. Little is known at present on the function of this gene - Progranulin - and further investigation will hopefully reveal new aspects of the disease and potential novel therapeutic targets.
To understand the function of disease-associated genes both in health and disease, various animal models were generated that include soil worms (Caenorhabditis elegans), flies (Drosophila melanogaster), Zebrafish and mice. These models either carry the human mutated gene ('knock-in' models) or have the animal counterpart of the human gene specifically ablated ('knock-out' models). Detailed anatomical and behavioural analysis of these animal models provided important clues about the mechanism of disease and about the function of the gene under physiological and pathological conditions.
An additional strategy that we exploited to understand the function of specific genes linked to disease was to identify the binding partners of the encoded protein. To carry out their specific task in the cell, proteins need to interact with several other proteins, and identifying those partners can provide clues on the metabolic pathways where they participate and therefore on their cellular function. We carried out different approaches to pinpoint binding partners of a number of disease-associated proteins and we also determined whether and how specific mutations affected those interactions. An example is the beta-secretase, the function of which has been within the APOPIS Consortium clarified. This enzyme is one of the most important proteins in Alzheimer disease and as such one it is a most promising target for future therapeutic approaches.
The data that we obtained from animal models combined with those from protein interactors have substantially contributed to our understanding of the function of genes involved in neurodegenerative disorders. And the more we know about these genes, the higher the possibilities for therapeutic intervention. Thus, by knowing in detail what the disease-linked protein does in the nerve cell, in which cellular location, with which partners it has to interact to carry out its specific function and how mutations affect these processes offer different steps where specific compounds could act to prevent or correct the disease.

Improving clinical detection of neurodegenerative diseases
Prof. Christoph Hock, University of Zurich
In most neurodegenerative diseases diagnosis is made once symptoms are well established and therefore when substantial brain damage has already occurred. There is therefore an urgent need for early diagnosis to be able to treat the diseases before brain damage is irreversible. There is also a need for good 'biological markers', substances that can be easily detected in patients and whose presence indicates a particular disease state.
In the APOPIS Consortium we invested significant efforts to identify very early changes that occur in these diseases, i.e. before symptoms commence. One major tool that we used to detect such changes is brain imaging, which provides a non-invasive and reproducible method to analyse the structure and function of the brain of living patients. We focussed on young healthy subjects that are at high risk of developing a neurodegenerative condition latter in life because of a positive family history. For Alzheimer disease for example, we were able to detect changes in the brain that occur decades before the disease is manifested. We studied a family in which the age for the clinical manifestation of Alzheimer disease is ~50 years. Brain imaging analysis of a 20 years-old individual from this family who carries the mutation revealed increased brain activity when compared with subjects with the same age that do not carry the mutation. This increased brain activity probably reflects a compensatory effort to overcome neuronal dysfunction caused by first pathological changes.
Because brain imaging can be performed in the same patient at different time points as the disease progresses, we were able to identify specific patterns of brain alterations characteristic of some diseases. This represents a major advance, since some neurodegenerative disorders present similar or overlapping clinical symptoms. The brain imaging tools developed in APOPIS should then help clinicians make a more accurate diagnosis and therefore administer more adequate treatments.
APOPIS efforts were also centred in the identification of biomarkers; specific molecules present in the body fluids of patients (like blood or cerebral spinal fluid that are easily accessible) but not in healthy individuals or in patients affected by a different neurodegenerative condition. Thus for example by comparing the protein profile of CSF taken from healthy and diseased individuals we were able to identify 6 novel biomarker candidates that are either increased or decreased in samples from AD patients.
In conclusion, in the APOPIS Consortium we achieved important advances in various brain imaging techniques and in biological markers that should aid in early and accurate diagnose and allow monitoring disease progression. Moreover, these can be used in clinical trials to assess the efficacy of treatments, to evaluate the capacity of a drug to slow down or prevent disease onset.

Therapy of neurodegenerative diseases
Prof. Roger M. Nitsch, University of Zurich
There is a huge medical need for causal treatments of neurodegenerative conditions. Available symptomatic treatments can at best delay disease progression and temporarily ameliorate some of the clinical signs. Thus, considerable efforts in the APOPIS Consortium focused in the development of novel therapeutic approaches for the treatment and eventual prevention of neurodegenerative diseases.
Because many neurodegenerative disorders have in common the presence of abnormal protein aggregates in the brain, prevention of aggregate formation was a common therapeutic objective. We developed assays that allowed us to test thousands of compounds for their anti-aggregation capacity. Positive candidates identified in these screenings were subsequently tested in cellular assays to identify those with the ability to reduce not only protein aggregation but also toxicity. Interestingly, some candidates were effective against more than one amyloidogenic protein, i.e. against huntingtin and Abeta that accumulate in the brains of Huntington and Alzheimer disease patients, respectively. The most promising candidates were then evaluated in small animal models and shown to be effective in preventing aggregate-induced neurodegeneration. These compounds with therapeutic potential against a range of neurodegenerative disorders are currently being optimized to improve their brain penetration upon intravenous or intra-peritoneal injection. Additional promising anti-aggregation compounds developed in the Consortium are those described by Prof. de Strooper. These compounds (indeed D-peptides) were specifically 'designed' to bind to the amyloidogenic portion of a protein as identified with the amyloid pattern mentioned above. They were active in cell cultures and are currently tested in animal models.
A rather revolutionizing approach to treat neurodegenerative diseases emerged a few years ago and consists in vaccinating patients with the same protein that accumulates in their brains. The idea is to induce an immune reaction that eventually leads to the clearance of the deposits. Immunotherapy was first tested as an approach to treat Alzheimer disease, but the clinical trial had to be stopped due to brain inflammation in ~6% of the vaccinated patients. APOPIS members participated in this trial and were the first to show that despite the unwanted side effects there was a clear beneficial effect of immunotherapy. In the APOPIS Consortium we developed an alternative immunotherapy approach that should reduce or abolish the negative side effects observed in the initial clinical trial.
In conclusion, in the APOPIS Consortium we have developed novel anti-aggregation compounds (small chemical compounds and biologicals) that have promising therapeutic potential and guarantee further investigation.

Genes affecting Parkinson disease
Prof. Ralf Baumeister, Albert-Ludwigs-Universität Freiburg
Parkinson disease (PD) is the most common movement disorder and the second most common neuro-degenerative disease. It affects about 1% of the population over 65 years of age. The main hallmark of this devastating disease is the selective loss of neurons producing the neurotransmitter dopamine.
The APOPIS Consortium includes some of the leading European research laboratories studying the molecular mechanisms underlying the Parkinson pathology. APOPIS researchers contributed to under-standing the role of several genes involved in the disease – all of them have just recently been identified. In a study published this year in “The New England Journal of Medicine”, they could for example show for the first time that a particular mutation in the gene LRRK2, responsible for a familial form of Parkinson, may be important in some human populations in North Africa, while it is rarely observed throughout the world. These results will allow diagnosing Parkinson by genetic analysis and offering genetic counselling, in particular in these high-risk communities.
APOPIS researchers established a several laboratory models to analyse the role of LRRK2 and other genes affecting Parkinson. They could demonstrate that the majority of these genes are involved in the stress management of cells, and can interact with signals that may also regulate cell death and neuronal aging. Their results suggest that the defects causing Parkinson may interfere with an important genetic program whose normal biological function is to control the survival and lifespan of cells.
Among other animal models, research in APOPIS firmly established the only 1 mm long nematode worm Caenorhabditis elegans, a prime model for senescence and aging studies, as an important animal for studying Parkinson mechanisms and for testing drugs. Using a technique similar to that invented by the recipients of this year’s Nobel Prize in medicine, Craig Mello and Andrew Fire, a high-throughput test was developed to find target genes for the development of anti-Parkinson’s medication. With the same goal in mind, APOPIS mouse researchers also succeeded in identifying a receptor protein called RET whose function is critical for the survival of those neurons affected by Parkinson.
Three years of APOPIS research have considerably improved the understanding of the various factors contributing to the onset of Parkinson disease. Based on APOPIS research results, several chemical compounds have now been synthesized whose effects are currently being tested in the contributing laboratories.

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PUBLICATIONS
(team leader in bold)

2004

Bimonte M, Gianni D, Allegra D, Russo T, Zambrano N (2004) Mutation of the feh-1 gene, the Caenorhabditis elegans orthologue of mammalian Fe65, decreases the expression of two acetylcholinesterase genes. Eur J Neurosci 20:1483-8.

De Pietri Tonelli D, Mihailovich M. Di Cesare A, Codazzi F, Grohovaz F, Zacchetti D (2004) Translational regulation of BACE-1 expression in neuronal and non-neuronal cells. Nucl Acids Res 32:1808-17.

Edbauer D, Kaether C, Steiner H, Haass C (2004) Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1. J Biol Chem 79:37311-5.

Griffiths TD, Warren JD (2004) What is an auditory object? Nature Reviews Neurosci 5:887-92.

Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, van Duinen SG, Maat-Schieman MLC, Staufenbiel M, Mathews PM, Jucker M (2004) Abeta is targeted to a vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954-60.

Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 25(9440):1169-71.

Nitsch RM (2004) Immunotherapy of Alzheimer disease. Alzheimer Dis Assoc Disord 18:185-9.

Rademakers R, Cruts M, Van Broeckhoven C (2004) The role of Tau in frontotemporal dementia and related tauopathies. Hum Mutat 24: 277-95.

Repetto E, Russo C, Venezia V, Nizzari M, Nitsch RM, Schettini G (2004) BACE1 overexpression regulates amylois precursor protein cleavage and interaction with the ShcA adapter. Ann NY Acad Sci 1030:330-8.

Sleegers K, Roks G, Theuns J, Aulchenko YS, Rademakers R, Cruts M, van Gool WA, Van Broeckhoven C, Heutink P, Oostra BA, Van Swieten JC, van Duijn CM (2004) Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain 127(7):1641-9.

Venezia V, Russo C, Repetto E, Nizzari M, Marchetti B, Schettini G (2004) Apoptotic cell death and Amyloid Precursor Protein signaling in neuroblastoma SH-SY5Y cells. Ann NY Acad Sci 1030:339-47.

Venezia V, Russo C, Repetto E, Salis S, Dolcini V, Genova F, Nizzari M, Mueller U, Schettini G (2004) Apoptotic cell death influences the signaling activity of the Amyloid Precursor Protein through ShcA and Grb2 adaptor proteins in neuroblastoma SH-SY5Y cells. J Neurochem 90:1359-70.

Zambrano N, Gianni D, Bruni P, Passaro F, Telese F, Russo T (2004) Fe65 is not involved in the platelet-derived growth factor-induced processing of Alzheimer's amyloid precursor protein, which activates its caspase-directed cleavage. J Biol Chem 279: 16161-69.

2005

Barbato C, Canu N, Zambrano N, Serafino A, Minopoli G, Ciotti MT, Amadoro G, Russo T, Calissano P (2005) Interaction of tau with Fe65 links tau to APP. Neurobiol Dis 18(2):399-408.

Benmoyal-Segal L, Vander T, Shifman S, Bryk B, Ebstein R, Marcus EL, Stessman J, Darvasi A, Herishanu Y, Friedman A, Soreq H (2005) Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson's disease. FASEB J 19(3):452-4.

Bevilacqua MA, Iovine B, Zambrano N, D'Ambrosio C, Scaloni A, Russo T, Cimino F (2005) Fibromodulin gene tranbscription is induced by ultraviolet irradiation, and its regulation is impaired in senescent human fibroblasts. J Biol Chem 280(36):31809-17.

Blazejczyk M, Wojda U, Sobczak A, Spilker C, Bernstein HG, Gundelfinger ED, Kreutz MR, Kuznicki J (2005) Ca2+-independent binding and cellular expression profiles question a significant role of calmyrin in transduction of Ca2+-signals to Alzheimer's disease-related presenilin 2 in forebrain. Biochem Biophys Acta 1762(1):66-72.

Braun HA, Meusinger R, Schmidt B (2005) 2-Iodoethanols from aldehydes, diiodomethane and isopropyl-magnesium chloride. Tetrahedron Lett 46(15):2551-4.

Braun HA, Umbreen S, Groll M, Kuckelkorn U, Mlynarczuk I, Wiegand ME, Drung I, Kloetzel PM, Schmidt B (2005) Tripeptide mimetics inhibit the 20S proteasome by covalent bonding to the active site threonines. J Biol Chem 280(31):28394-401.

Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman MS, Haass C (2005) Gamma-secretase complex assembly within the early secretory pathway. J Biol Chem 280(8):6471-8.

Cisse MA, Sunyach C, Lefranc-Jullien S, Postina R, Vincent B, Checler F (2005) The disintegrin ADAM9 indirectly contributes to the physiological processing of cellular prion modulating ADAM10 activity. J Biol Chem 280(49):40624-31.

Coolen MW, Van Loo KM, Van Bakel NN, Pulford DJ, Serneels L, De Strooper B, Ellenbroek BA, Cools AR, Martens GJ (2005) Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders. Neuron 45(4):497-503.

Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, De Pooter T, De Rijk P, Del-Favero J, Van Broeckhoven C (2005) Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers multiple low copy repeats in the tau region. Hum Mol Gen 14(13):1753-62.

De Anda FC, Pollarolo G, Da Silva JS, Camoletto PG, Feigfuin F, Dotti CG (2005) Centrosome localization determines neuronal polarity. Nature 436(7051):704-8.

De Strooper B (2005) Nicastrin: Gatekeeper of the gamma-secretase complex. Cell 122(3):318-20.

Dermaut B, Kumar-Singh S, Rademakers R, Theins J, Cruts M, Van Broeckhoven C (2005) Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends in Genetics 21(12):664-72.

Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Camaco IE, Marjaux E, Craessaerts K, Roebroek AJ, Schwake M, D'Hooge R, Bach P, Kalinke U, Moechars D, Alzheimer C, Reiss K, Saftig P, De Strooper B (2005) Phenotypic and biochemical analyses of BACE1 and BACE2 deficient mice. J Biol Chem 280(35):30797-806.

Esteras Chopo A, Serrano L, Lopez de la Paz M (2005) The amyloid stretch hypothesis: Recruiting proteins toward the dark side. Proc Natl Acad Sci USA 102(46):16672-7.

Fassa A, Mehta P, Efthimiopoulos S (2005) Notch 1 interacts with the amyloid precursor protein in a numb-independent manner. J Neurosci Res 82:214-25.

Fotinopoulou A, Tsachaki M, Vlavaki M, Poulopoulos A, Rostagno A, Frangione B, Ghiso J, Efthimiopoulos S (2005) BRI2 interacts with APP and regulates As production. J Biol Chem 280(35):30768-72.

Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nature Medicine Vol 11(3):252-3.

Hoglinger GU, Lannuzel A, Escobat Khondiker M, Michel PP, Duyckaerts C, Feger J, Champy P, Prigent A, Medja F, Lombes A, Oertel WH, Ruberg M, Hirsch EC (2005) The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy. J Neurochem 95(4):930-9.

Kalvodova L, Kahya N, Schwille P, Ehehalt R, Verkade P, Drechsel D, Simons K (2005) Lipids as modulators of proteolytic activity of BACE. J Biol Chem 280(44):36815-23.

Krawitz P, Haffner C, Fluhrer R, Steiner H, Schmid B, Haass C (2005) Differential localization of a critical aspartate suggests a non-redundant proteolytic function of the presenilin homologues SPPL2b and SPPL3. J Biol Chem 280(47):39515-23.

Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C (2005) Dense-Core Plaques in Tg2576 and PSAPP Mouse Models of Alzheimer's Disease Are Centered on Vessel Walls. Am J Pathol 167(2):527-43.

Lefranc-Jullien S, Lisowski V, Hernandez JF, Martinez J, Checler F (2005) Design and characterization of a new cell-permeant inhibitor of the s-secretase BACE1. Br J Pharmacol 145(2):228-35.

Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, Tazir M, Leutenegger AL, Guimaraes J, Bonnet AM, Agid Y, Durr A, Brice A (2005) G2019S LRRK2 mutation n French and North African families with Parkinson’s disease. Ann Neurol 58(3):brief communications

Lesage S, Leutenegger AL, Ibanez P, Janin S, Lohmann E, Durr A, Brice A, and the French Parkinson’s Disease Genetics Study Group (2005) LRRK2 haplotype analyses in European and North-African families with Parkinson’s disease: a common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet 77:330-2.

Leyssen M, Ayaz D, Hebert S, Reeve S, De Strooper B, Hassan BA (2005) Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J 24(16):2944-55.

Ligios C, Sigurdson CJ, Santucciu C, Carcassola G, Manco G, Basagni M, Maestrale C, Cancedda MG, Maudau L, Aguzzi A (2005) PrPSc in mammary glands of sheep affected by scrapie and mastitis. Nat Med 11(11):1137-8.

Likeman M, Anderson VM, Stevens JM, Waldman AD, Godbolt AK, Frost C, Rossor MN, Fox NC (2005) Arch Neurol 62(9):1410-5.

Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, De Strooper B, Hartmann D, Saftig P (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and {beta}-catenin translocation. Proc Natl Acad Sci USA 102 (26):9182-7.

Meshorer E, Biton IE, Ben-Shaul Y, Ben-Ari S, Assaf Y, Soreq H, Cohen Y (2005) Chronic cholinergic imbalanaces promote brain diffusion and transport abnormalities. FASEB J 19:910-22.

Papassotiropoulos A, Lambert JC, Wavrant-De Vrieze F, Wollmer MA, von der Kammer H, Streffer JR, Alessia M, Huynh KD, Wolleb S, Lutjohann D, Schneider B, Thal DR, Groimaldi LME, Tsolaki M, Kapaki E, Ravid R, Konietzko U, Hegi T, Pasch T, Jung H, Braak H, Amouyel P, Rogaev EI, Hardy J, Hock C, Nitsch RM (2005) Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease. Neurodegener Dis 2(5):233-41.

Pardossi-Piquard R, Petit A, Kawarai T, Sunyach C, Alves da Costa C, Vincent B, Ring S, D'Adamio L, Shen J, Muller U, St. George Hyslop P, Checler F (2005) Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprisylin by intracellular domains of sAPP and APLP. Neuron 46:541-54.

Pastor MT, Esteras-Chopo A, Lopez de la Paz M (2005) Design of model systems for amyloid formation: lessons for prediction and inhibition. Curr Opin Struct Biol 15(1):57-63.

Periquet M, Corti O, Jacquier S, Brice A (2005) Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J Neurochem 95(5):1259-76.

Prokop S, Haass C, Steiner H (2005) Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of the presenilin fragments. J Neurochem 94:57-62.

Rademakers R, Cruts M, Sleegers K, Dermaut B, Theuns J, Aulchenko Y, Weckx S, De Pooter T, Van den Broeck M, Corsmit E, De Rijk P, Del-Favero J, van Swieten J, van Duijn CM, Van Broeckhoven C (2005) Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in Dutch population-based sample. Am J Hum Gent 77:634-52.

Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P, Baker M, Sleegers K, Crook R, De Pooter T, Bel Kacem S, Adamson J, Van den Bossche D, Van den Broeck M, Gass J, Corsmit E, De Rijk P, Thomas N, Engelborghs S, Heckman M, Litvan I, Crook J, De Deyn PP, Dickson D, Schellenberg GD, Van Broeckhoven C, Hutton ML (2005) High-density SNP haplotyping suggest altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 14(21):3281-92.

Rademakers R, van der Zee J, Kumar-Singh S, Dermaut B, Cruts M, Van Broeckhoven C (2005) Chromosome 17-linked frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. In: IPSEN Meeting Research and Perspectives in Alzheimer's disease: Genotype - proteotype - phenotype relationships in neurodegenerative diseases. eds: Cummings J, Hardy J, Poncet M, Christen Y (Springer):117-37.

Raoul C, Abbas-Terki T, Bensadoun JC, Guillot S, Haase G, Szle J, Henderson CE, Aebischer P (2005) Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nature Medicine 11(4):423-8.
Reinhard C, Hebert S, De Strooper B (2005) The amyloid-beta precursor protein: integrating structure with biological function. EMBO J 24(23):3996-4006.

Reiss K, Maretzky T, Ludwig A, Tousseyn T, De Strooper B, Hartmann D, Saftig P (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. EMBO J 24(4):742-52.

Russo C, Venezia A, Repetto E, Nizzari M, Violani E, Carlo P, Schettini G (2005) The amyloid precursor protein and its network of interacting proteins: physuilogical and pathological implications. Brain Res Reviews 48:257-64.

Sala C, Roussignol G, Meldolesi J, Fagni L (2005) Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis and dendritic spines in hippocampal neurons. J Neurosci 25:4587-92.

Santos da Silva J, Hasegawa T, Miyagi T, Dotti CG, Abad-Rodriguez J (2005) Asymmetric membrane ganglioside sialidase activity specifies axonal fate. Nature Neuroscience 8(5):606-15.

Schmidt B, Narlawar R, Braun H (2005) Drug Development and PET-Diagnostics for Alzheimer's Disease. Current Medicinal Chemistry 12: 763-81.

Serneels L, Dejaegere T, Craessaerts K, Horre K, Jorissen E, Toussey T, Hebert S, Coolen M, Martens G, Zwijsen A, Annaert W, Hartmann D, De Strooper B (2005) Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci USA 102(5): 1719-24.

Sillen A, Leroy A, Wieruszeski JM, Loyens A, Beauvillain JC, Buée L, Landrieu I, Lippens G (2005) Regions of tau implicated in the paired helical fragment core as defined by NMR. Chem Bio Chem 6:1849-56.

Springer W, Hoppe T, Schmidt E, Baumeister R (2005) A Caenorhabditis elegans Parkin mutant with altered solubility couples a-synuclein aggregation to proteotoxic stress. Hum Mol Gen 14(22):3407-23.

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2006

Alves da Costa C, Sunyach C, Pardossi-Piquard R, Sevalle J, Vincent B, Boyer N, Kawarai T, Girardot N, St George-Hyslop P, Checler F (2006) Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J Neurosci 26(23):6377-85.

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Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, Serneels S, Kamali K, Corsmit E, De Leenheir E, Martin JJ, De Deyn PP, Van Broeckhoven C, Theuns J (2006) Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease. Brain 129(11):2984-91.

Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, van Duijn CM, De Deyn PP, Van Broeckhoven C, Dermaut B (2006) The UBQLN1 polymorphism, UBQ-8i, at 9q22 is not associated with Alzheimer's disease with onset before 70 years. Neurosci Lett 392(1-2):72-4.

Buée L, Delacourte A (2006) Tauopathy and Alzheimer disease: a full degenerating process. Psychol NeuroPsychiatr Vieil 4(4):261-73.

Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K, Metzger K, Frezza C, Annaert W, D'Adamio L, Derks C, Dejaegere T, Pelegrine L, D'Hooge R, Scorrano L, De Stooper B (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristal remodelling. Cell 126(1):163-75.

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Codazzi F, Di Cesare A, Chiulli N, Albanse A, Meyer T, Zacchetti D, Grohovaz F (2006) Synergistic control of protein kinase gamma activity by ionotropic and metabotropic glutamate receptor inputs in hippocampal neurons. J Neurosci 26(13):3404-11.

Crameri A, Biondi E, Kuehnle K, Lutjohann D, Thelen KM, Perga S, Dotti CG, Nitsch RM, Ledesma MD, Mohajeri MH (2006) The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo. EMBO J 25(2):432-43.

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Da Costa CA, Dunys J, Brau F, Wilk S, Cappai R, Checler F (2006) 6-hydroxy-dopamine but not 1-methyl-4phenylpiridinium abolishes alpha-synuclein anti-apoptotic phenotype by inhibiting its proteasomal degradation and by promoting its aggregation. J Biol Chem 281(14):9824-31.
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Di Cesare A, Del Piccolo P, Zacchetti D, Grohovaz F (2006) EP(2) receptor stimulation promotes calcium responses in astrocytes via activation of the adenylyl cyclase pathway. Cell Mol Life Sci 63 (21):2546-53.

Doglio LE, Kanwar R, Jackson GR, Perez M, Avila J, Dingwall C, Dotti CG, Fortini MW, Feiguin F (2006) gamma-cleavage-independent functions of presenilin, nicastrin and Aph.1 regulate the molecular organization of cell junctions and prevent tau toxicity in vitro. Neuron 50 (3):359-75.

Dunys J, Kawarai T, Wilk S, St. George-Hyslop P, Alves da Costa C, Checler F (2006) Catabolism of endogenous and overexpressed APH1a and Pen-2. Evidence for artefactual involvement of the proteasome in the degradation of overexpressed proteins. Biochem J 394(2):501-9.

Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE (2006) Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet 15(18):2743-51.

Esteras-Chopo A, Pastor MT, Lopez de la Paz M (2006) Peptide model systems for amyloid fiber formation. Design strategies and validation methods. In: Walker JM (ed) Protein Design: Methods in Molecular Biology, Medicine and Biotechnology 340:253-76.

Falcone S, Cocucci E, Podini P, Kirchhausen T, Clementi E, Meldolesi J (2006) Macropinocytosis: regulated co-ordination of endocytic and exocytic membrane traffic events. J Cell Sci 119 (Pt22):4758-69.

Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, Cimino F (2006) p53 suppresses the Nrf2-dependent transcription of antioxidant response gens. J Biol Chem 281(52):39776-84.

Fluhrer R, Grammer G, Israel L, Condron MM, Haffner C, Friedmann E, Bohland C, Imhof A, Martoglio B, Teplow B, Haass C (2006) A gamma-secretase like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b. Nat Cell Biol 8(8):894-6.

Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Daniel NN, De Strooper B, Scorrano L (2006) OPA1 controls apoptotic cistae remodelling independently from mitochondrial fusion. Cell 126(1):177-89.

Galas MC, Dourlen P, Begard S, Ando K, Blum D, Hamdane M, Buée L (2006) The peptidyl prolyl cis/trans isomerase pin1 modulates stress-induced dephosphorylation of tau in neurons: Implications in a pathological mechanism related to Alzheimer’s disease. J Biol Chem 281(28):19296-304.

Giaime E, Sunyach C, Herrant M, Grosso S, Auberger P, McLean PJ, Checler F, Alves da Costa C (2006) Caspase 3-derived C-terminal product of synphilin-1 displays anti-apoptotic function via modulation of the p53-dependent cell death pathway. J Biol Chem 281(17):11515-22.

Giedraitis V, Hedlund M, Skoglund L, Blom E, Ingvast S, Brundin R, Lannfelt L, Glaser A (2006) New Alzheimer's disease locus on chromosome 8. J Med Genet 43(12):931-5.

Gijselinck I, Bogaerts V, Rademakers R, van der Zee J, Van Broeckhoven C, Cruts M (2006) Visualization of MAPT inversion on stretched chromosomes of tau-negative frontotemporal dementia patients. Hum Mutat 27:1057-9.

Goedert M, Spillantini MG (2006) A century of Alzheimer's disease. Science 314:777-81.

Hamdane M, Dourlen P, Bretteville A, Sambo AV, Ferreira S, Ando K, Kerdraen O, Begard S, Geay L, Lippens G, Sergeant N, Delacourte A, Maurage CA, Galas MC, Buée L (2006) Pin1 allows for differential tau dephosphorylation in neuronal cells. Mol Cell Neurosci 32(1-2):155-60.

Hampe C, Ardila-Osorio H. Fournier M, Brice A, Corti O (2006) Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum Mol Genet 15(13):2059-75.

Hebert SS, Serneels L, Tolia A, Craessaerts K, Derks C, Filippov MA, Muller U, De Strooper B (2006) Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep 7(7):739-45.

Herbst M, Wanker E (2006) Therapeutic approaches to polyglutamine diseases: Combating protein misfolding and aggregation. Curr Pharm Des 12(29):2543-55.

Herranz H, Milan M (2006) Notch and affinity boundaries in Drosophila. BioEssays 28(2):113-6.

Herranz H, Stamataki E, Feguin F, Milan M (2006) Self-refinement of Notch activity through the transmembrane protein Crumbs: modulation of gamma-secretase activity. EMBO Rep 7(3):297-302.

Herzig MC, Nostrand WE, Jucker M (2006) Mechanism of cerebral b-amyloid angiopathy: murine and cellular models. Brain Pathol 16(1):40-54.

Ibanez P, Lesage S, Lohmann S, Thobois S, De Michele G, Borg E, Agid M, Durr A, Brice A, and the French Parkinson's Disease Genetics Study Group (2006) Mutational analysis of the PINK1 gene in early-onset Parkinsonism from Europe and North Africa. Brain 129(3):686-94.

Ishihara L, Warren L, Gibson R, Amouri R, Lesage S, Durr A, Tazir M, Wszolek ZK, Uitti RJ, Nichols WC, Griffith A, Hattori N, Leppert D, Watts R, Zabetian CP, Foroud TM, Farrer MJ, Brice A, Middleton L, Hentati F (2006) Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations. Arch Neurol 63:1250-4.

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Johansson AS, Berglin-Dehlin F, Karlsson G, Edwards G, Gellersfors P, Lannfelt L (2006) Physiochemical charac-terization of the Alzheimer's disease-related peptides Abeta 1-42Arctic and Abeta 1-42wt. FEBS J 273(12):2618-30.

Jozwiak K, Zekanowski C, Filipek S (2006) Linear patterns of Alzheimer’fs disease mutations along a-helices of presenilins as a tool for PS-1 model construction. J Neurochem 98:1560-72.

Knobloch M, Konietzko U, Krebs DC, Nitsch RM (2006) Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging 28(9):1297-306.

Kramer ER, Knott L, Su F, Dessaud E, Krull CE, Helmbacher F, Klein R (2006) Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb. Neuron 50(1):35-47.

Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, Cruts M, Dermaut B, Wang R, Van Broeckhoven C (2006) Mean age-of-onset of familial Alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat 27(7):686-95.

Larbig G, Pickhardt M, Lloyd DG, Schmidt B, Mandelkow E (2006) Screening for inhibitors of tau protein ag-gregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold holding. Curr Alzheimer Res 4(3):315-22.

Larbig G, Schmidt B (2006) A facile synthesis of tetramic and tetronic acids as beta-secretase inhibitors. J Comb Chem 8(4):480-90.

Lefranc-Jullien S, Sunyach C, Checler F (2006) APPepsilon, the epsilon-secretase-derived N-terminal product of the beta-amyloid precursor protein, behaves as a type I protein and undergoes alpha-, beta-, and gamma-secretase cleavages. J Neurochem 97(3):807-17.

Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A, and the French Parkinson's Disease Genetics Study Group (2006) LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Engl J Med 354:422-3.

Lippens G, Sillen A, Smet C, Wieruszeski JM, Leroy A, Buée L, Landrieu I (2006) Studying the natively unfolded neuronal tau protein by solution NMR spectroscopy. Protein Pept Lett 13(3):235-46.

Lord A, Kalimo H, Eckman C, Zhang XQ, Lannfelt L, Nilsson LNG (2006) The Arctic Alzheimer mutation facili-tates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice. Neurobiol Aging 27(1):67-77.

Lorusso A, Covino C, Priori G, Bachi A, Meldolsei J, Chieregatti E (2006) Annexin2 coating the surface of enlargoeosomes is needed for their regulated exocytosis. EMBO J 25 (23):5443-56.

Meshorer E, Soreq H (2006) Virtues and woes of AChE alternative splicing in stress-related neuropathologies. Trends Neuriosci 29 (4):216-24.

Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313(5794):1781-4.

Mondadori CR, Buchmann A, Mustovic H, Schmidt CF, Boesiger P, Nitsch RM, Hock C, Streffer J, Henke K (2006) Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years. Brain 129(Pt11):2908-22.

Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C, Nitsch RM, Papassotiropoulos A, Henke K (2006) Better memory and neural efficiency in young apolipoprotein E{varepsilon}4 carriers. Cereb Cortex 17(8):1934-47.

Narlawar R, Perez Revuelta BI, Baumann K, Schubenel R, Haass C, Steiner H, Schmidt B (2007) N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase. Bioorg Med Chem Lett 17(1):176-82.

Pardossi-Piquard R, Dunys J, Yu G, George-Hyslop PST, Alves da Costa C, Checler F (2006) Neprilysin activity and expression are controlled by nicastrin. J Neurochem 97(4):1052-6.

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Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M (2006) Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7(9):940-6.

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Schindowski K, Bretteville A, Leroy K, Begard S, Brion JP, Hamdane M, Buée L (2006) Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169(2): 599-616.

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Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn C, Van Broeckhoven C (2006) APP duplication is sufficient to cause early-onset Alzheimer dementia with cerebral amyloid angiopathy. Brain 129: 2977-83.

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2007

APOPIS Consortium
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Bender FL, Fischer M, Funk N, Orel N, Rethwilm A, Sendtner M (2007) High-efficiency gene transfer into cultured embryonic motoneurons using recombinant lentiviruses. Histochem Cell Biol 127(4):439-48.

Blom ES, Holmans P, Arepalli S, Adighibe O, Hamshere ML, Gatz M, Pedersen NL, Bergem AL, Owen MJ, Hollingworth P, Goate A, Williams J, Lannfelt L, Hardy J, Wavrant-De Vrieze F, Glaser A (2007) Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13? Am J Med Genet B Neuropsychiatr Genet 147B(6):778-83.

Caratu G, Allegra D, Bimonte M, Schiattarella GG, D’fAmbrosio C, Scaloni A, Napolitano M, Russo T, Zambrano N (2007) Identification of the ligands of protein interaction domains through a functional approach. Mol Cell Proteomics 6(2):333-45.

Chiulli N, Codazzi F, Di Cesare A, Gravaghi C, Zacchetti D, Grohovaz F (2007) Sphingosylphosphocholine effects on cultured astrocytes reveal mechanisms potentially involved in neurotoxicity in Niemann-Pick typa A disease. Eur J Neurosci 26(4):875-81.

Cocucci E, Racchetti G, Podini P, Meldolesi J (2007) Enlargeosome traffic: exocytosis triggered by various signals is followed by endocytosis, membrane shedding or both. Traffic 8(6):742-57.

De Ferrari GV, Papassotiropoulos A, Biechele T, Wavrant De Vrieze F, Avila ME, Major MB, Myers A, Saez K, Henriques JP, Zhao A, Wollmer MA, Nitsch RM, Hock C, Morris CM, Hardy J, Moon RT (2007) Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc Natl Acad Sci USA 104(22):9434-9.

Domingues SCTS, Henriques AG, Wu W, da Cruz e Silva EF, da Cruz e Silva OA (2007) Altered subcellular distribution of the Alzheimer's amyloid precurosr protein under stress conditions. Ann NY Acad Sci 1096:184-95.

Dunys J, Kawarai T, Sevalle J, Dolcini V, St George-Hyslop P, Alves da Costa C, Checler F (2007) p53-dependent Aph-1 and Pen-2 anti-apoptotic phenotype requires the integrity of the gamma-secretase complex but is independent of its activity. J Biol Chem 282(149):10516-25.

Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, Lannfelt L, Pettersson FE (2007) Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem 103(1):334-45.

Escobar-Khondiker M, Hollerhage M, Muriel MP, Champy P, Bach A, Depienne C, Respondek G, Yamada ES, Lannuzel A, Yagi T, Hirsch EC, Oertel WH, Jacob R, Michel PP, Ruberg M, Hoglinger GU (2007) Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci 27(29): 7827-37.

Galliciotti G, Glatzerl M, Kinter J, Kozlov SV, Cinelli P, Rulicke T, Sonderegger P (2007) Accumulation of mutant neuroserpin precedes development of clinical symptoms in familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol 170(4):1305-13.

Gorner K, Holtorf E, Waak J, Pham TT, Vogt-Weisenhorn DM, Wurst W, Haass C, Kahle PJ (2007) Structural determinants of the C-terminal helix-kink-helix motif essential for protein stability and survival promoting activity of DJ-1. J Biol Chem 282(18):13680-91.

Henriques AG, Vieira SI, Rebelo S, Domingues SC, da Cruz e Silva EF, da Cruz e Silva OA (2007) Isoform specific amyloid-beta protein precursor metabolism. J Alzheimers Dis 11(1):85-95.

Hoglinger GU, Breunig JJ, Depboylu C, Rouaux C, Michel PP, Alvarez-Fischer D, Bouitillier AL, DeGregori J, Oertel WH, Rakic P, Hirsch EC, Hunot S (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proc Natl Acad Sci USA 104(9):3585-90.

Johansson AS, Garlind A, Berglind-Dehlin F, Karlsson G, Edwards K, Gellerfors P, Ekholm-Petterson F, Palmblad J, Lannfelt L (2007) Docosahexaenoic acid stabilzes soluble amyloid-beta protofibrils and sustains amlyoid-beta-induced neurotoxicity in vitro. FEBS J 274(4): 990-1000.

Kaeser SA, Herzig MC, Coomaraswamy J, Kilger E, Selenica ML, Winkler DT, Staufenbiel M, Levy E, Grubb A, Jucker M (2007) Cystating C modulates cerebral s-amyloidosis. Nat Genet 39(12):1437-9.

Kramer ER, Aron L, Ramakers GMJ, Seitz S, Zhuang X, Beyer K, Smidt MP, Klein R (2007) Absence of Ret signaling in mice causes progessive and late degeneration of the nigrostriatal system. PloS Biol 5(3):e39.

Le Ber I, van der Zee J, Hannequin D, Gijselinck I, Campion D, Puel M, Laquerriere A, De Pooter T, Camuzat A, Van den Broeck M, Dubois B, Sellal F, Lacomblez L, Vercelleto M, Thomas-Anterion C, Michel BF, Golfier V, Didic M, Salachas F, Duycchaerts C, Cruts M, Verpillat P, Van Broeckhoven C, Brice A (2007) Progranulin null mutations in both sporadic and familial frontotemporal dementia. Hum Mutat 28(9):846-55.

Lesage S, Magali P, Lohmann E, Lacomblez L, Teive H, Janin S, Cousin PY, Durr A, Brice A, and the French Parkinson Disease Genetics Study Group (2007) Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism. Hum Mutat 28(1):27-32.

Lesage S, Janin S, Lohmann E, Leutenegger AL, Viallet F, Pollak P, Durif F, Thobois S, Layet V, Vidailhet M, Agid Y, Durr A, Brice A, and the French Parkinson's Disease Genetics Study Group (2007) LRRK2 exon 41 mutations in European sporadic Parkinson's disease. Arch Neurol 64(3):425-30.

Luque CM, Milan M (2007) Growth control in the proliferative region of the Drosophila eye-head primordium: The elbow-noc gene complex. Dev Biol 301(2):327-39.

Maruszak A, Safranow K, Gacia M, Gabryelewicz T, Slowik A, Styczynska M, Peplonska B, Golan MP, Zekanowski C, Barcikowska M (2007) Sigma receptor type 1 gene variation in a group of Polish patients with Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord 23(6):432-8.

Mihailovich M, Thermannn R, Grohovaz F, Hentze MW, Zacchetti D (2007) Complex translational regulation on BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region. Nucleic Acids Res 35(9):2975-85.

Minopoli G, Stante M, Napolitano F, Telese F, Aloia L, De Felice M, Di Lauro R, Pacelli R, Brunetti A, Zambrano N, Russo T (2007) Essential roles of Fe65, Alzheimer’s amyloid precursor binding protein, in the cellular response to DNA damage. J Biol Chem 282(2):831-5.

Narlawar R, Revuelta BI, Haass C, Steiner H, Schmidt B, Baumann K (2007) Scaffold of the cyclooxygenase-2 (COX.2) inhibitor carprofen provides Alzheimer gamma-secretase modulators. J Med Chem 49(26):7588-91.

Narlawar R, Perez Revuelta BI, Baumann K, Schubenel R, Haass C, Steiner H, Schmidt B (2007) N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase. Bioorg Med Chem Lett 17(1):176-82.

Nizzari M, Venezia V, Bianchini B, Caorsi V, Diaspro A, Repetto E, Thellung S, Corsaro A, Schettini G, Carlo P, Florio T, Russo C (2007) Amyloid precursor protein and presenilin 1 interaction studied by FRET in human H4 cells. Ann NY Acad Sci 1096:249-57.

Rami L, Loy CT, Hailstone J, Warren JD (2007) Odour identification in frontotemporal lobar degeneration. J Neurol 254(4):431-5

Rebelo S, Vieira SI, Esselmann H, Wiltfang J, da Cruz e Silva EF, da Cruz e Silva OA (2007) Tyr687 dependent APP endocytosis and Abeta production. J Mol Neurosci 32(1):1-8.

Sahlin C, Lord A, Magnusson K, Englund H, Almeida CG, Greengard P, Nyberg F, Gouras GK, Lannfelt L, Nilsson LN (2007) The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase. J Neurochem 101(3):854-62.

Schindowski K, Belarbi K, Bretteville A, Ando K, Buée L (2007) Neurogenesis and cell cycle-reactivated neuronal death during pathogenic tau aggregation. Genes Brain Behav 7(1):92-100.

Schindowski K, Belarbi K, Buée L (2007) Review: Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes Brain Behav 7(1):43-56.

Schupbach M, Lohmann E, Anheim M, Lesage S, Czernecki V, Yaici S, Worbe Y, Charles P, Welter ML, Pollak P, Durr A, Agid Y, Brice A (2007) Subthalamic nucleus stimulation is efficacious in patients with Parkinsonism and LRRK2 mutations. Mov Disord 22(1):119-22.

Sunyach C, Alfa Cisse M, Alves da Costa C, Voncent B, Checler F (2007) The C-terminal products of cellular prion protein processing C1 and C2 exert distinct influence on p53-dependent stauropirine-induced caspase-3 activation. J Biol Chem 282(3):1956-63.

Tuite MF, Cox BS (2007) The genetic control of the forrmation and propagation of the [PSI+] prion of yeast. Prion 1(2)101-9.

Van Broeck B, Van Broeckhoven C, Kumar-Singh S (2007) Current insights into molecular mechnisms of Alzheimer disease and their implication for therapeutic approaches. Neurodegener Dis 4(5):349-65.

Venezia V, Nizzari M, Repetto E, Violani E, Corsaro A, Thellung S, Villa V, Carlo P, Schettini G, Florio T, Russo C (2007) Amyloid precursor protein modulates ERK1/2 signaling. Ann NY Acad Sci 1090:455-65.

Whitwell JL, Sampson EL, Loy CT, Warren JE, Rossor MN, Fox NC, Warren J (2007) VBM signatures of abnormal eating behaviours in frontotemporal lobar degeneration. NeuroImage 35(1):207-13.

Wollmer MA, Sleegers K, Ingelsson M, Zekanowski C, Brouwers N, Maruszak A, Brunner F, Huynh KD, Kilander L, Brundin RM, Hedlund M, Giedraitis V, Glaser A, Engelborghs S, De Deyn PP, Kapaki E, Tsolaki M, Daniilidou M, Molyva D, Paraskevas GP, Thal DR, Barcikowska M, Kuznicki J, Lannfelt L, Van Broeckhoven C, Nitsch RM, Hock C, Papassotiropoulos A (2007) Association study of cholesterol-related genes in Alzheimer's disease. Neurogenetics 8(3):179-88.

2008

Ermini FV, Grathwohl S, Radde R, Yamaguchi M, Staufenbiel M, Palmer TD, Jucker M (2008) Neurogenesis and alterations of neural stem cells in mouse models of cerebral amyloidosis. Am J Pathol 172(6):1520-8.

Esteras-Chopo A, Pastor MT, Serrano L, Lopez de la Paz M (2008) New strategy for the generation of specific D-peptide amyloid inhibitors. J Mol Biol 377(5): 1372-81.

Lesage S, Lohmann E, Tison F, Durif F, Durr A, Brice A, and the French Parkinson's Disease Genetics Study Group (2008) Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet 45(1):43-6.

O'Callaghan P, Sandwall E, Li JP, Yu H, Ravid R, Guan ZZ, van Kuppevelt TH, Nilsson LN, Ingelsson M, Hyman BT, Kalimo H, Lindahl U, Lannfelt L, Zhang X (2008) Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contribzed by glial cells. Brain Pathol 18(4):548-61.

Pastor MT, Kummerer N, Schubert V, Esteras-Chopo A, Dotti CG, Lopez de la Paz M, Serrano L (2008) Amyloid toxicity is independent of polypeptide sequence, length and chirality. J Mol Biol 375(3):695-707.

Rebelo S, Vieira SI, da Cruz e Silva EF, da Cruz e Silva OA (2008) Monitoring “D“APP synthesis by taking advantage of the reversible effect of cycloheximide. Am J Alzheimers Dis Other Demen 23(6):602-8.

Skoglund L, Vitanen M, Kalimo H, Lannfelt L, Jonhagen ME, Ingelsson M, Glaser A, Herva R (2008) The tau S305S mutation causes frontotemporal dementia with parkinsonism. Eur J Neurol 15(2):156-61.

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis. Science 319(5870):1668-72.

Sundelof J, Giedraitis V, Irizarry MC, Ingelsson E, Ronnemaa E, Arnlov J, Gunnarsson MD, Hyman BT, Basun H, Ingelsson M, Lannfelt L, Kilander L (2008) Plasma beta amyloid and the risk of Alzheimer disease and dementia in elderly men: a prospective, population-based cohort study. Arch Neurol 65(2):256-63.

Ulusoy A, Bjorklund T, Hermening S, Kirik D (2008) In vivo gene delivery for development of mammalian models for Parkinson's disease. Exp Neurol 209(1):89-100.

2009

Baumannn F, Pahnke J, Radovanovic I, Rülicke T, Tolnay M, Aguzzi A (2009) Functionally relevan domains of the prion identified in vivo. PloS One 4(9):e6707.

Baumann S, Höttecke N, Schubenel R, Baumann K, Schmidt B (2009) NSAID-derived gamma-secretase modulators. Part III: anchoring. Bioorg Med Chem Lett 19(24):6986-90.
Belarbi K, Schindowski K, Burnouf S, Caillerez R, Grosjean ME, Demeyer D, Hamdane M, Sergeant N, Blum D,
Buée L
(2009) Early tau pathology involving the septo-hippocampal pathway in a tau transgenic model: relevance to Alzheimer’s disease. Curr Alzheimer Res 6(2):152-7.

Blom ES, Giedraitis V, Arepalli S, Hamshere ML, Adighibe O, Goate A, Williams J, Lannfelt L, Hardy J, Vrièze VW, Glaser A (2009) Further analysis of previously implicated linkage regions for Alzheimer’s disease in affected relative pairs. BMC Med Genet 10:122.

Bretteville A, Ando G, Ghestem A, Loyens A, Bégard S, Beauvillain JC, Sergeant N, Hamdane M, Buée L (2009) Two-dimensional electrophoresis of tau mutants reveals specific phosphorylation pattern likely linked to early tau conformational changes. PloS One 4(3):e4843.

D’Alessandro R, Klajn A, Meldolesi J (2009) Expression of dense-core vesicles and of their exocytosis are governed by the repressive transcription factor NRSF/REST. Ann NY Acad Sci 1152:194-200.

Da Cruz e Silva OA, Rebelo S, Vieeira SI, Gandy S, da Cruz e Silva EF, Greengard P (2009) Enhanced generation of Alzheimer’s amyloid-beta following chronic exposure to phorbol ester correlates with differential effects on alpga and epsilon isozymes of protein kinase C, J Neurochem 108(2):319-30.

Dunys J, Sevalle J, Gaimae E, Pardossi-Piquard R, Vitek MP, Renbaum P, Levy-Lahad E, Zhang YW, Xu H, Checler F, da Costa CA (2009) p53-dependent control of transactivation of the Pen2 promoter by presenilins. J Cell Sci 122(Pt 21):4003-8.

Fournier M, Vitte J, Garrique J, Langui D, Dullin JP, Saurini F, Hanoun N, Perez-Diaz F, Cornilleau F, Joubert C, Ardila-Osorio H, Traver S, Duchateau R, Goujet-Zalc C, Paleologou K, Lashuel HA, Haass C, Duyckaerts C, Cohen-Salmon C, Kahle PJ, Hamon M, Brice A, Corti O (2009) Parkin deficiency delays motor decline and disease manifestation in amouse model of synucleinopathy. PloS One 4(8):e6629.

Goodger ZV, Rajendran L, Trutzel A, Kohli BM, Nitsch RM, Konietzko U (2009) Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci 122(Pt 20):3703-14.

Henriques AG, Vieiera SI, Crespo-López ME, Guiomar de Oliveira MA, da Cruz e Silva EF, da Cruz e Silva OA (2009) Intracellular sAPP retention in response to Abeta is mapped to cytoskeleton-associated structures. J Neurosci Res 87(6):1449-61.

Ibanez P, Lesage S, Janin S, Lohmann E, Durif F, Destée A, Bonnet AM, Brefel-Courbon C, Heath S, Zelenika D, Agid Y, Dürr A, Brice A, and the French Parkinson’s Disease Genetic Study Group (2009) Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch Neurol 66(1):102-8.

Lohmann E, Thobois S, Lesage S, Brousolle E, du Montcel ST, Ribeiro MJ, Remy P, Pelissolo A, Dubois B, Mallet L, Pollak P, Agid Y, Brice A, and the French Parkinson’s Disease Genetics Study Group (2009) A multidisciplinary study of patients with early-onset PD with and without parkin mutations. Neurology 72(2):110-6.

Lohmann E, Leclerc L, De Anna F, Lesage S, Dubois B, Agid Y, Dürr A, Brice A, and the French Parkinson’s Disease Genetic Study Group (2009) A clinical, neuropsychological and olfactory evaluation of a large family with LRRK2 mutations. Parkinsonism Relat Disord 15(4):273-6.

Pardossi-Piquard R, Dunys J, Giaime E, Guillot-Sestier MV, St Geoge-Hyslop P, Checler F, Alves da Costa C (2009) p53-dependent control of cell death by nicastrin: lack of requirement for presenilin-dependent gamma-secretase complex. J Neurochem 109(1):225-37.

Rönnemaa E, Zethelius B, Sundelö J, Sundström J, Degerman-Gunnarsson M, Lannfelt L, Berne C, Kilander L (2009) Glucose metabolism and the risk of Alzheimer’s disease and dementia: a population-based 12 year follow-up study in 71-year-old men. Diabetologia 52(8):1504-10.

Rohrer JD, Warren JD, Rossor MN (2009) Abnormal laughter-like vocalisations replacing speech in primary progressive aphasia. J Neurol Sci 284(1-2):120-3.

Skoglund L, Brundin R, Olofsson T, Kalimo H, Ingvast S, Blom ES, Giedraitis V, Ingelsson M, Lannfelt L, Basun H (2009) Frontotemporl dementia in a large Swedish family is caused by a progranulin null mutation. Neurogenetics 10(1):27-34.

Sousa VL, Bellani S, Giannandrea M, Yousuf M, Valtorta F, Meldolesi J, Chieregatti E (2009) {alpha}-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Mol Biol Cell 20(16):3725-39.

Vieira SI, Rebelo S, Domingues SC, da Cruz e Silva EF, da Cruz e Silva OA (2009) S655 phosphorylation enhances APP secretory traffic. Moll Cell Biochem 328(1-2):145-54.

Vintém AP, Henriques AG, da Cruz e Silva OA, da Cruz e Silva EF (2009) PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer’s disease. Neurotoxicol Teratol 31(2):85-8.

Willuweit A, Velden J, Godemann R, Manook A, Jetzek F, Tintrup H, Kauselmann G, Zevnik B, Henriksen G, Drzezga A, Pohlner J, Schoor M, Kemp JA, von der Kammer H (2009) Early-onset robust amyloid pathology in a new homozygous mouse model of Alzheimer’s disease. PloS One 4(11):e7931.

Zhou D, Zambrano N, Russo T, D’Adamio L (2009) Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signaling. J Alzheimers Dis 16(2):301-7.

2010

Bellani S, Sousa VL, Ronzitti G, Valtorta F, Meldolesi J, Chieregatti E (2010) The regulation of a synaptic function by alpha-synuclein. Commun Integr Biol 3(2):106-9.

Blom ES, Wang Y, Skoglund L, Hansson AC, Ubaldi M, Lourdusamy A, Sommer WH, Mielke M, Hyman BT, Heilig M, Lannfelt L, Nilsson LN, Ingelsson M (2010) Increased mRNA levels of TCF7L2 and MYC of the Wnt pathway in Tg-ArcSwe mice and Alzheimer’s disease brain. Int J Alzheimers Dis 2011:936580.

Hänggi J, Buchmann A, Monadori CR, Henke K, Jäncke L, Hock C (2010) Sexual dimorphism in the parietal substrate associated with visuospatial cognition independent of general intelligence. J Cogn Neurosci 22(1):139-55.

Petzold A, Chapman MD, Schraen S, Verwey NA, Pasquier F, Bombois S, Brettschenider J, Fox NC, von Arnim CA, Teunissen C, Pijnenburg Y, Riepe MW, Otto M, Tumani H, Scheltens P, Buée L, Rossor MN (2010) An unbiased, staged, multicentre, validation strategy for Alzheimer’s disease CSF tau levels. Exp Neurol 223(2):432-8.

2011

Benedict C, Jacobsson JA, Rönnemaa E, Sällman-Allmén M, Brooks S, Schultes B, Fredriksson R, Lannfelt L, Kilander L, Schiöth HB (2011) The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men. Neurobiol Aging 32(6):1159.e1-5.

Bettegazzi B, Mihailovich M, Di Cesare A, Consonni A, Macco R, Pelizzoni I, Codazzi F, Grohovaz F, Zacchetti D (2011) beta-secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression. Eur J Neurosci 33(2):236-43.

Hänggi J, Streffer J, Jäncke L, Hock C (2011) Volumes of lateral temporal and parietal structures distinguish between healthy aging, mild cognitive impairment, and Alzheimer’s disease. J Alzheimers Dis 26(4):719-34.

Hänggi J, Mondadori CR, Buchmann A, Henke K, Hock C (2011) A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects. Neurobiol Aging 32(6):1023-32.

Kulic L, Wollmer MA, Rhein V, Pagani L, Kuehnle K, Cattepoel S, Tracy J, Eckert A, Nitsch RM (2011) Neurobiol Aging 32(10):1827-38.

Meldolesi J (2011) Neurite outgrowth: this process, first discovered by Santiago Ramon y Cajal, is sustained by the exocytosis of two distict types of vesicles. Barin Res Rev 66(1-2):246-55.

Van der Jeugd A, Ahmed T, Burnouf S, Belarbi K, Hamdane M, Grosjean ME, Humez S, Balschun D, Blum D, Buée L, D’Hooge R (2011) Hippocampal tauopathy in tau transgenic mice coincides with impaired hipoocampus-dependent learning and memory, and attenuated late-phase long-term depression of synpatic transmission. Neurobiol Learn Mem 95(3):296-304.

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair JP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, and RNA processing protein, cause familial Amyotrophic lateral sclerosis type 6. Science 323:1208-11.

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