Memory Loss in Alzheimer Disease:
Underlying Mechanisms and Therapeutic Targets

Grant Agreement:
Duration: 1 January 2008 – 30 June 2011
Total project costs: 4,360,102 EUR | EU contribution: 2,998,696 EUR

Contractors: VERUM - Stiftung für Verhalten und Umwelt, München, Germany | VIB - Vlaams Instituut voor Biotechnologie, Leuben, Belgium | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., München, Germany | Université de Lille II - Droit et Santé, France | University College Dublin, Ireland | Ludwig-Maximilians-Universität München, Germany | Albert-Ludwigs-Universität Freiburg, Germany | Universitat Autònoma de Barcelona, Spain | Katholieke Universiteit Leuven, Belgium | Senexis Ltd, Cambridge, United Kingdom

OBJECTIVES: The project was structured in four scientific work packages (WP). WP1 and WP2 focused, respectively, on the characterization of the Abeta and tau assemblies that disrupt signalling pathways essential for synaptic plasticity and memory, and on the identification of those pathways. WP3 addressed the mechanistic link between Abeta and tau, while WP4 finally focused on target validation and the pre-clinical evaluation of Abeta- and tau-anti-aggregation therapeutic strategies.
Insoluble aggregates of Abeta and tau provide the pathological hallmarks of Alzheimer’s disease (AD) and the two proteins act in combination to cause synaptic misfunction, memory loss and finally neuronal death. However, the molecular mechanisms underlying these effects are not completely understood. Therefore, MEMOSAD aimed at defining the molecular mechanisms of Abeta- and tau-induced synaptotoxicity and at developing disease-modifying therapeutics for the prevention of memory loss in AD. The specific objectives were: (1) to define precisely the toxic Abeta and tau species responsible for memory loss in AD, (2) to elucidate the mechanisms of Abeta- and tau-mediated toxicity that are at the basis of memory loss, (3) to define the mechanistic link between Abeta and tau that brings about memory loss, and (4) to translate the biological findings into effective, disease-modifying therapeutic strategies.

In WP1 we characterized Abeta preparations of various origins, identified the effect of these well-defined Abeta preparations on synapses and memory, and characterized the signalling pathways underlying Abeta-induced toxicity. We generated in vitro amyloid fibrils using ‘synthetic’ Abeta40 and Abeta42 peptides and demonstrated that for toxicity the quality (40 to 42 ratio) is more relevant than the absolute quantity of peptide. Indeed, in AD the Abeta40/42 ratio changes from 9:1 (physiologic) to ~7:3. We showed that Abeta at pathologic Abeta40/42 7:3 ratio, contrary to physiologic (9:1) ratio: (i) forms fibrils in vitro with a longer ‘oligomeric’ phase, (ii) affects synaptic function of neurons grown on microchips, (iii) suppresses long-term potentiation (LTP) in brain slices, and (iv) prevents memory formation when injected into rat brain. Thus, Abeta species that are quantitatively similar but qualitatively different can have very different effects on neurons in vivo. We also characterized Abeta from post-mortem human brains. Interestingly, we identified phosphorylation of Abeta monomers and dimers in human AD brains that opens up novel avenues to investigate its role in AD. We also showed a very interesting correlation between soluble Abeta monomer and SDS-stable Abeta dimer and Braak staging, suggesting that these two Abeta species are linked to aberrant tau metabolism. When injected in brain of naïve rats, brain-Abeta preparations prevented memory consolidation and decreased by ~40% synaptic density in the hippocampal dentate gyrus (brain region important for memory and largely affected in AD). The effect on synapses was further analysed in vitro using synthetic Abeta preparations. At Abeta40/42 ratios of 7:3 Abeta mainly co-localized with synaptophysin (synaptic marker), while such staining was not observed at 9:1 and 10:0 ratios. Extensive washing of neurons did not modify the staining and did not restore synaptic activity for several hours, indicating the rather irreversible nature of the binding. The effect of Abeta on LTP was also demonstrated with brain-derived Abeta. Abeta-injection, but not injection of non-AD brain extract, strongly inhibited LTP. It was recently shown that prion protein (PrPC) is required for plasticity impairment mediated by Abeta assemblies. We thus tested pre-injection of an antibody against PrPC 96-104 (putative Abeta-binding region). The inhibition of LTP by the human brain extract was fully abrogated. Finally, we used APP J9 mice [Hsia AY et al., 1999. Proc Natl Acad Sci USA 96(6):3228-33] to gain knowledge on signalling pathways affected by Abeta. Memory deficits in these mice start at 6 months of age, coinciding with Abeta accumulation and prior to plaques formation. Memory deficits in APP J9 transgenic mice are associated with a specific decrease of CREB target genes related to synaptic plasticity and memory. This decrease is detected at 6- but not at 2-months. Extensive analysis of APP J9 mice-derived neurons indicates that Abeta affects the dephosphorylation (and thus activation) of the CREB transcriptional co-activator CRTC1 (also called TORC1) but not CREB phosphorylation. Thus, deficient CRTC1 dephosphorylation as a result of Abeta accumulation causes CREB-dependent transcriptional deficits and memory deficits.

In WP2 we investigated the effect of expressing tau variants in various models: neuronal cells, brain slices, zebrafish, C. elegans and mice. We used an inducible cell model of tau pathology (N2A cells) to study tau aggregation, degradation and the generation of tau toxicity. We demonstrated that the proteolysis of tau plays an important role in tau aggregation and toxicity. Indeed, tau proteolysis may generate amyloidogenic tau fragments that initiate the aggregation. Enhanced aggregation leads to enhanced toxicity. Autophagy was identified as an important contributor to tau degradation. We also investigated tau toxicity in zebrafish. Tau-transgenic zebrafish recapitulate key pathological features of AD including tau phosphorylation and aggregation, cell death and behavioural disturbances. Axonal transport of mitochondria is greatly reduced in these animals and can be rescued by co-expression of MARK, suggesting that microtubule binding by tau is necessary for transport inhibition. Inhibition of mitochondria axonal transport by mutant tau was also observed in a transgenic C. elegans model of tauopathy. Mitochondria accumulated in the proximal part of the axons in these worms. The zebrafish and C. elegans data support a model that tau-induced pathogenesis is at least partially caused by axonal transport defects. Too, we characterized tau transgenic mouse lines available in the consortium. Thy-tau22 mice [Schindowski K et al., 2006. Am J Pathol 169(2):599-616] display tau pathology in the absence of motor dysfunction. Long-term potentiation and depression (LTP and LTD) as well as memory formation are affected in these mice. These mice present in addition non-cognitive neuropsychiatric disorders characteristic of AD. Various tau transgenic lines in which expression of tau can be switched on and off [Eckermann K et al., 2007. J Biol Chem 282(43):31755-65/Mocanu MM et al., 2008. J Neurosci 28(3):737-48] were characterized. Tau ‘pro-aggregation’ mice display impairments in hippocampus-dependent behaviour as well as hippocampal LTP and these deficits are reversed by switching off the expression of the tau transgene. Histopathologically, during the tau expression phase the hyperphosphorylation and aggregation of tau is accompanied by a loss of neurons and synapses. Almost no pathology is observed in anti-aggregation mice. When the expression of tau is discontinued, there is no visible recovery of tau aggregation and neuronal loss, however, there is partial recovery of synapses, what may explain the recovery of LTP. Interestingly, the remaining tau aggregates in switched-off mice consist of endogenous mouse tau whereas the human tau is no longer visible. This suggests that the tau aggregates are in a dynamic equilibrium with their subunits and that normal tau can form aggregates if “poisoned”.

In WP3 we studied the synergy between Abeta and tau and its consequences on neuronal and synaptic damage and on memory loss. We also investigated the relevance of tau in the Abeta-induced damage.
We showed that toxic Abeta oligomers added to cultures of WT hippocampal neurons cause a disruption of the axonal sorting machinery and a redistribution of endogenous tau into soma and dendrites. Tau redistribution is one of the earliest signs of neuronal degeneration in AD. Missorting affects not only tau, but also other axonal markers such as neurofilaments, and correlates with a dramatic local decrease of microtubules. In the missorted dendritic regions there was a depletion of spines and spine-related proteins. Thus Abeta oligomers evoke responses that disrupt the axonal sorting machinery; they allow endogenous tau to enter dendrites and to destroy spines and microtubules locally. This is in analogy to the loss of spines and microtubules observed in AD. Abeta oligomers also seem to induce tau kinases specific for the KXGS motifs in tau repeats (MARK, p70S6K, BRSK/SADK), the consequent tau phosphorylation and dissociation from microtubules. By contrast, most proline-directed kinases tested (MAPK, JNK, GSK3b, but not cdk5), all considered to be involved in the pathological phosphorylation of tau in AD, showed little change upon Abeta treatment. Interestingly, Abeta preparations with toxic Abeta40/Abeta42 ratio (7:3) are ~10 times more potent in inducing tau-related changes than an ADDL preparation (contains monomers, dimers, trimers and some high molecular weight aggregates). And only ‘mild’ effects were observed with Abeta dimer preparations. Finally, other cell stressors such as oxidative stress, serum deprivation, excitotoxicity and extracellular ATP, caused a similar effect as the Abeta oligomers treatment, namely tau missorting, local disappearance of spines and microtubules, and increased tau phosphorylation. Thus, missorting of tau seems to be a general response of neurons to diverse types of stress, one of them being the Abeta oligomers. We performed a similar analysis of Abeta-induced changes using neurons derived from tau knock-out mice. There was a notable difference in the response of neurons to Abeta and other cell stressors. Tau KO neurons were less inhibited by Abeta with regard to spontaneous activity, they were less affected in terms of loss of dendritic microtubules or missorting of neurofilaments, even though Abeta oligomers were similarly directed to bind to synapses. A major difference was that the loss of spines was less pronounced, arguing that tau plays a role in the Abeta-induced synaptic loss. We next analysed the effect of Abeta preparations on synapses in vitro (MEA chip assay) and the relevance of tau in the Abeta-mediated toxic effects. WT and tau KO hippocampal neurons were grown at the same cell density on microchips and the rate of neural firing was compared before and after addition of Abeta preparations with different Abeta42/40 ratios. Overall, tau KO networks were ~50% less susceptible to Abeta42/40 10:0 and 3:7 inhibitory effects than the WT cultures, and were not sensitive to Abeta42/40 0:10 and 1:9, similar to WT neurons. Altogether, we revealed a mechanism of Abeta toxicity in neurons and demonstrated the relevance of tau as a mediator of Abeta-induced toxicity.

WP4 focused on four topics: (i) validation of candidate therapeutic targets, and the pre-clinical evaluation of novel therapeutic strategies, (ii) Abeta anti-aggregation, (iii) tau-anti-aggregation, (iv) tau immunotherapy. A number of candidate therapeutic targets were identified in the consortium including: autophagy as main system for degradation of tau (N2A cells); de-ubiquitinases as contributors to tau toxicity (C. elegans); decrease levels of the CREB co-activator CRTC1 as mediator of the Abeta-induced memory deficits (neurons from APP J9 transgenic mice); and cholesterol-modifying enzymes whose levels change in tau-transgenic mice (Thy-tau22) upon voluntary exercise and concomitant with memory improvements. We validated these candidate targets as follows: autophagy enhancers (like trehalose) reduced the level of aggregated tau and the concomitant tau toxicity in the N2A cell model; down-regulation of the de-ubiquitinase CYLD-1 in worms improved the tau-associated defects; adenoviral-mediated gene transfer of CRTC1 in the hippocampus of APP J9 mice significantly ameliorated the early learning and memory impairments; and viral-mediated expression of CPY46A1 (encoding an enzyme involved in brain cholesterol efflux) in the hippocampus of Thy-tau22 mice improved memory deficits. In addition, we validated in different models the modulation of tau phosphorylation as a relevant therapeutic treatment in AD. Most notably, treatment of Tau AD mice with selenium (an agonist of the tau phosphatase PP2A) could rescue the behavioural and hippocampal synaptic plasticity defects. Interestingly, Se2+ treatment also improved synaptic plasticity defects of APP/PS1 mice. Thus, the beneficial effect of Se2+ is not only apparent in tau-transgenic but also in a different AD model that do not over-express tau.

We generated in the consortium a number of small molecule (non-peptidic) Abeta anti-aggregation inhibitors. Importantly, oral doses of the compounds improved memory performance in two rodent models: rats upon intra-cerebroventricular injection of Abeta oligomers (acute model) and APP/PS1 double transgenic mouse model. The compounds were also effective in preventing the Abeta-induced decrease in synaptophysin levels in primary neuronal cultures. Interestingly, reduction in synaptophysin levels is a feature of AD that correlates with cognitive decline.
We also generated in the consortium tau anti-aggregation compounds (from the rhodanine class and from the phenylthiazolyl-hydrazide (PTH) class). So far the compounds were validated in a C. elegans model of taupathy. The compounds significantly improved the movement defects and the abnormal changes in neuronal morphology. Pre-clinical validation in mice is pending. Importantly, we validated an alternative strategy targeting tau. Immunization of Thy-tau22 mice against the ser422 tau epitope generated an immune response specific for this epitope, reduced aggregated tau and delayed cognitive deficits. Thus, tau immunotherapy may be a useful therapeutic strategy for AD and other tauopathies.

We had proposed to deliver by the end of the project 3 or 4 validated therapeutic targets and at least 2 compounds with demonstrated therapeutic efficacy in mouse models of AD. Among the targets identified and validated in the consortium the most relevant are: the Aph1B subunit of gamma-secretase; the CREB-co-activator CRTC1 (or TORC1); the tau ser422 epitope; toxic ratios of Abeta40 to Abeta42 (10:0, 7:3); autophagy. We also generated non-peptidic Abeta aggregation inhibitors (like SEN1428 and SEN1500) and demonstrated their beneficial effects on memory tasks in two different murine models (Abeta-injected rats and APP/PS1 transgenic mice). Finally and even if not proposed in the initial Grant Application, we validated tau immunotherapy (against tau ser422) as a useful therapeutic strategy for AD and other tauopathies. Large-scale drug screening efforts focusing on the validated targets will be done in a follow-up of MEMOSAD, in collaboration with the pharmaceutical industry. The targets identified or other components of the signalling cascades where they participate may have an additional value as biomarkers with a potential use as diagnostic tools.

BENEFITS: The data obtained is also of relevance for other neurodegenerative disorders, notably those involving tauopathy and synaptic loss (e.g., Parkinson's disease, Pick's disease, frontotemporal dementia, etc.). Therefore, the project is expected to have an impact on various societal levels: (i) on the health of European citizens by contributing to an early diagnosis of AD, and the development and validation of new therapies for treatment and prevention of a so far incurable brain disease; (ii) on Europe’s economy, if medical treatment can successfully delay symptoms by a few years and, thus, substantially decrease the economic burden of AD - measured as productivity loss by affected individuals and caregivers as well as by the burden on Europe’s health care systems; (iii) on Europe's competitiveness and the innovative capacity of its health-related industries by contributing to stop loosing the major role as a global centre for biomedical research, evidenced in the last decades especially in comparison to the US and Japan.

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PUBLICATIONS (team leaders in bold)


Tolia A, Horré K, De Strooper B (2008) Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of gamma-secretase. J Biol Chem 283(28): 19793-803. doi: 10.1074/jbc.M802461200 (free article)

Dejaegere T, Serneels L, Schäfer MK, Van Biervliet J, Horré K, Depboylu C, Alvarez-Fischer D, Herreman A, Willem M, Haass C, Höglinger GU, D’Hooge R, De Strooper B (2008) Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. PNAS 105 (28): 9775-9780. doi: 10.1073.pnas.0800507105 (free article in PubMed Central )

Schraen-Maschke S, Sergeant N, Dhaenens CM, Bombois S, Deramecourt V, Caillet-Boudin ML, Pasquier F, Maurage CA, Sablonnière B, Vanmechelen E, Buée L (August) Tau as biomarker of neurodegenerative diseases. Biomarkers Med 2(4): 363-84. doi: 10.2217/17520363.2.4.363 (free article in PubMed)

Wakabayashi T & De Strooper B (2008) Presenilins: members of the gamma-secretase quartets, but part-time soloists too. Physiology 23(4): 194-204. doi: 10.1152/physiol.00009.2008 (free article)


Bulic B, Pickhardt M, Schmidt B, Mandelkow EM, Waldmann H, Mandelkow E (2009) Development of tau aggregation inhibitors for Alzheimer’s disease. Angew Chem Int Ed Engl 48(10): 1740-52. doi: 10.1002/anie.200802621

Bretteville A, Ando K, 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. doi:10.1371/journal.pone.0004843 (free article in PubMed Central)

Belarbi K, Schindowski K, Burnouf S, Caillerez R, Grosjean ME, Demeyer D, Hamdane M, 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. doi: - (free article in PubMed)

Schraen-Maschke S, Dhaenens CM, Bombois S, Deramecourt V, Van Brussel E, Obriot H, Marzys C, Sergeant N, Maurage CA, Pasquier F, Sablonnière B, Buée L (2009) Les marqueurs biologiques de la maladie Alzheimer: quel intérêt pour un diagnostic moins tardif? Revue Neurologique 165(HS2): 97-103. doi: RN-04-09-165-HS2-0035-3787-101019-200901998

Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horré K, Van Houtvin T, Esselmann H, Paul S, Schäfer MK, Berezovska O, Hyman BT, Sprangers B, Sciot R, Moons L, Jucker M, Yang Z, May PC, Karran E, Wiltfang J, D'Hooge R, De Strooper B (2009) gamma-secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 324(5927):639-42. doi: 10.1126/science.1171176 (free article in PubMed)

Paquet D, Bhat R, Sydow A, Mandelkow EM, Berg S, Hellberg S, Fälting J, Distel M, Köster RW, Schmid B, Haass C (2009) A zebrafish model of tauopathy allows in vivo imaging og neuronal cell death and drug evaluation. J Clin Invest 119(5): 1382-95. doi: 10.1172/JCI37537 (free article in PubMed Central)

Sämann J, Hegermann J, von Gromoff E, Eimer S, Baumeister R, Schmidt E (2009) Caenorhabditis elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite overgrowth. J Biol Chem 284(24):16482-91. doi: 10.1074/jbc.M808255200 (free article)

Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Gen 18(21): 4153-70. doi: 10.1093/hmg/ddp367 (free article)

Shankar GM & Walsh DM (2009) Alzheimer's disease: synaptic dysfunction and Abeta. Mol Neurodeger (4): 48. doi: 10.1186/1750-1326-4-48 (free article in PubMed Central)


Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2010) Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy 6(1):182-3. doi: 10.4161/auto.6.1.10815 (free article)

Bergmans BA & De Strooper B (2010) Gamma-secretases: from cell biology to therapeutic strategies. Lancet Neurol 9 (2): 215-226. doi:10.1016/S1474-4422(09)70332-1

De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Naurol 6(2): 99-107. doi: 10.1038/nrneurol.2009.218 (free article in PubMed Central)

España J, Giménez-Llort L, Valero J, Miñano A, Rábano A, Rodriguez-Alvarez J, Laferla FM, Saura CA (2010) Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer's disease transgenic mice. Biol Psychiatry 67(6): 513-21. doi: 10.1016/j.biopsych.2009.06.015

Sydow S, Mandelkow EM (2010) ‘Prion-like’ propagation of mouse and human tau aggregates in an inducible mouse model of tauopathy. Neurodegener Dis 7(1-3):28-31. doi: 10.1159/000283479

Paquet D, Schmid B, Haass C (2010) Transgenic zebrafish as a novel model to study tauopathies and other neurodegeneraive disorders in vivo. Neurodegener Dis 7(1-3):99-102. doi: 10.1159/000285515

Wang Y, Krüger U, Mandelkow E, Mandelkow EM (2010) Generation of tau aggregates and clearance by autophagy in an inducible cell model of tauopathy. Neurodegener Dis 7(1-3):103-7. doi: 10.1159/000285516

Mc Donald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, Selkoe DJ, Ince PG, Walsh DM (2010) The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain 133(Pt 5):1328-41. doi: 10.1093/brain/awq065 (free article)

Saura CA (2010) Presenilin/gamma-secretase and inflammation. Front Aging Neurosci 2:16. doi:10.3389/fnagi.2010.00016 (free article in PubMed Central)

Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I (2010) Role of presenilins in neuronal calcium homeostasis. J Neurosci 30(25): 8566-80. doi: 10.1523/JNEURISCI.1554-10.2010 (free article in PubMed)

España J, Valero J, Miñano-Molina AJ, Masgrau R, Martín E, Guardia-Laguarta C, Lleó A, Giménez-Llort L, Rodríguez-Alvarez J, Saura CA (2010) Beta-amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci 30(28):9402-10. doi:10.1523/JNEUROSCI.2154-10.2010 (free article)

Buée L, Troquier L, Burnouf S, Belarbi K, Van der Jeugd A, Ahmed T, Fernandez-Gomez F, Caillerez R, Grosjean ME, Begard S, Barbot B, Demeyer D, Obriot H, Brion I, Buée-Scherrer V, Maurage CA, Balschun D, D’Hooge R, Hamdane M, Blum D, Sergeant N (2010) From tau phosphorylation to tau aggregation: what about neuronal death? Biochem Soc Trans 38(4):967-72.

Wang Y, Garg S, Mandelkow EM, Mandelkow E (2010) Proteolytic processing of tau. Biochem Soc Trans 38(4):955-61. doi: 10.1042/BST0380955

Van Bebber F, Paquet D, Hruscha A, Schmid B, Haass C (2010) Methylene blue fails to inhibit Tau and polyglutamine protein-dependent toxicity in zebrafish. Neurobiol Dis 39(3): 265-71. doi: 10.1016/nbd.2010.03.023

Jorissen E & De Strooper B (2010) Gamma-secretase and the intramembrane proteolysis of Notch. Curr Top Dev Bol 92:201-30. doi: 10.1016/S0070-2153(10)92006-1

Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca2+ elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30(36):11938-50. doi: 10.1523/NEUROSCI.2357-10.2010 (free article)

Bulic B, Pickhardt M, Mandelkow EM, Mandelkow E (2010) Tau protein and tau aggregation inhibitors. Neuropharmacology 59(4-5):276-89. doi: 10.1016/j.neuropharm.2010.01.016

Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D'Hooge R, Martins IC, Rousseau F, Schymkowitz J, De Strooper B (2010) Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta 40 ratio. EMBO J 29(19):3408-20. doi: 10.1038/emboj.2010.211

Hébert SS, Papadopoulou AS, Smith P, Galas MC, Planel E, Silahtaroglu AN, Sergeant N, Buée L, De Strooper B (2010) Genetic ablation of Dicer in adult forbrain neurons results in abnormal tau hyper-physphorylation and neurodegeneration. Hum Mol Genet 19(20):3959-69. doi: 10.1093/hmg/ddq311 (free article)

De Strooper B & Annaert W (2010) Novel research horizons fpr presenilins and gamma-secretase in cell biology and disease. Annu Rev Cell Dev Biol 26:235-60. doi:10.1146/annurev-cellbio-100109-104117


Shankar GM, Welzel AT, McDonald JM, Selkoe DJ, Walsh DM (2011) Isolation of low-n amyloid beta-protein oligomers from cultured cells, CSF, and brain. Methods Mol Biol 670:33-44. doi: 10.1007/978-1-60761-744-0_3

Sergeant N & Buée L (2011) Tau models. Animal Models of Dementia:449-68. doi: 10.1007/978-1-60761-898-0_23 (book chapter)

Sergeant N & Buée L (2011) Tau pathology. Cytoskeleton of the Nervous System; Advances in Neurobiology 3:83-132. doi: 10.1007/978-1-4419-6787-9_4 (book chapter)

Garg S, Timm T, Mandelkow EM, Mandelkow E, Wang Y (2011) Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment. Neurobiol Aging 32(1):1-14. doi: 10.1016/j.neurobiolaging.2010.09.008

Thathiah A & De Strooper B (2011) The role of G protein-coupled receptors in the pathology of Alzheimer’s disease. Nat Rev Neurosci 12(2):73-87. doi: 10.1038/nrn2977 (free article)

Valero J, España J, Parra-Damas A, Martín E, Rodríguez-Alvarez J, Saura CA (2011) Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APPSw,Ind transgenic mice. PLoS ONE 6(2):e16832. doi: 10.1371/journal.pone.0016832 (free article)

Sultan A, Nesslany F, Violet M, Bégard S, Loyens A, Talahari S, Mansuroglu Z, Marzin D, Sergeant N, Humez S, Colin M, Bonnefoy E, Buée L, Galas MC (February 2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 286(6):4566-75. doi: 10.1074/jbc.M110.199976

Sydow A, Van der Jeugd A, Zhen F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E,

D'Hooge R, Alzheimer C, Mandelkow EM (2011) Tau-induced defects in synaptic plasticity, learning and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci 31(7):2511-25. doi: 10.1523/JNEUROSCI.5245-10.2011

Welzel AT, Walsh DM (2011) Aberrant protein structure and diseases of the brain. Ir J Med Sci 180(1):15-22. doi: 10.1007/s11845-010-0606-2

Saura CA & Valero J (2011) The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 22(2):153-69. doi: 10.1515/RNS.2011.018

Van der Jeugd A, Ahmed T, Burnouf S, Belarbi K, Hamdame M, Grosjean ME, Humez S, Balschun D, Blum D, Buée L, D'Hooge R (2011) Hippocampal tauopathy in tau transgenic mice coincides with impaired hippocampus-dependent learning and memory, and attenuated late-phase long-term depression of synaptic transmission. Neurobiol Learn Mem 95(3):296-304. doi: 10.1016/nlm.2010.12.005

Zhou L, Chavez-Gutierrez L, Bockstael K, Sannerud R, Annaert W, May PC, Karran E, De Strooper B (2011) Inhibition of {beta]-secretase in vivo via antibody binding to unique loops (D and F) of BACE1. J Biol Chem 286(10):8677-87. doi: 10.1074/jbc.M110.194860 (free article)

Bammens L, Chavez-Gutierrez L, Tolia A, Zwijsen A, De Strooper B (2011) Functional and topological analysis of Pen-2, the fourth subunit of the gamma-secretase complex. J Biol Chem 286(14):12271-82. doi: 10.1074/jbc.M110.216978 (free article)

Lléo A, Saura CA (Epub) Gamma-secretase substrates and their implications for drug development in Alzheimer’s disease. Curr Top Med Chem 11(12):1513-27.

Barry AE, Klyubin I, McDonald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ (2011) Alzheimer’s disease brain-derived Abeta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci 31(20):7259-63. doi: 10.1523/JNEUROSCI.6500-10.2011

Belarbi K, Burnouf S, Fernandez-Gomez FJ, Laurent C, Lestavel L, Figeac M, Sultan A, Troquier L, Leboucher A, Caillerez R, Grosjean ME, Demeyer D, Obriot H, Brion I, Barbot B, Galas MC, Staels B, Humez S, Segeant N, Schraen-Maschke S, Muhr-Tailleux A, Hamdane M, Buée L, Blum D (2011) Beneficial effects of exercise in a transgenic mouse model of Alzheimer’s disease-like Tau pathology. Neurobiol Dis 43(2):486-94. doi: 10.1016/j.nbd.2011.04.022

Belarbi K, Burnouf S, Fernandez-Gomez F, Desmercieres J, Troquier L, Brouillette J, Tsambou L, Grosjean ME, Caillierez R, Demeyer D, Hamdane M, Schindowski K, Blum D, Buée L (2011) Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with Tau pathology? Curr Alzheimer Res 8(6):633-8. ISSN: 1567-2050

Li X, Kumar Y, Zempel H, Mandelkow EM, Biernat J, Mandelkow E (2011) Novel diffusion barrier for axonal retention of tau in neurons and its failure in neurodegeneration. EMBO J 30(23):4825-37. doi: 10.1038/emboj.2011.376

Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, D’Hooge R, Alzheimer C, Mandelkow EM (2011) Reversibility of tau-related cognitive defects in a regulatable FTD mouse model. J Mol Neurosci 45(3):432-7. doi: 10.1007/s12031-011-9604-5

Schirmer H, Adler H, Pickhardt M, Mandelkow E (2011) “Lest we forget you – methylene blue ...”. Neurobiol Aging 32(12):2325-7. doi: 10.1016/j.neurobiolaging.2010.12.012

Chong SA, Benilova I, Shaban H, De Strooper B, Devijver H, Moechard S, Eberle W, Bartic C, Van Leuven F, Callewaert G (2011) Synaptic dysfunction in hippocampus of transgenic mouse models in Alzheimer’s disease: a multi-electrode array study. Neurobiol Dis 44(3):284-91. doi: 10.1016/j.nbd.2011.07.006

Freir DB, Fedriani R, Scully D, Smith IM, Selkoe DJ, Walsh DM, Regan CM (2011) Abeta oligomers inhibit synapse remodelling necessary for memory consolidation. Neurobiol Aging 32(12):2211-8. doi: 10.1016/j.neurobiolaging.2010.01.001

Taghavi A, Nasir S, Pickhardt M, Haußen RH, Krause S, Mall G, Mandelkow E, Mandelkow EM, Schmidt B (2011) N’-benzylidene-benzohydrazides as novel and selcetive tau-PHF ligands. J Alzheimers Dis 27(4):835-43. doi: 10.3233/JAD-2011-111238

Timm T, von Kries JP, Li X, Mandelkow E, Mandelkow EM (2011) Microtubule affinity regulating kinase (MARK) activity in living neurons examined by a genetically encoded FRET/FLIM based biosensor: inhibitors with therapeutic potential. J Biol Chem 286(48):41711-22. doi: 10.1074/jbc.M111.257865 (free article)


Saura CA
(2012) CREB-regulated transcription coactivator 1-dependent transcriptuion in Alzheimer’s disease mice. Neurodegener Dis 10(1-4):250-2. doi: 10.1159/000333341

Zempel H, Mandelkow EM (2012) Linking amyloid-b and Tau: Amyloid-b induced synaptic dysfunction via local wreckage of the neuronal cytoskeleton. Neurodegener Dis 10(1-4):64-72. doi: 10.1159/000332816

Matenia D, Hempp C, Timm T, Eikhof A, Mandelkow EM (2012) Microtubule affinity regulating kinase 2 (MARK2) turns PTEN-induced kinase 1 (PINK1) on at T313, a mutation site in Parkinson’s disease: Effects on mitochondrial transport. J Biol Chem 287(11):8174-86. doi: 10.1074/jbc.M111.262287

Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D'Hooge R, Rodrigues CM (2012) TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol 45(3):440-54. doi: 10.1007/a12035-012-8256-y

Van der Jeugd A, Hochgräfe K, Ahmed T, Decker JM, Sydow A, Hofmann A, Wu D, Messing L, Balschun D, D'Hooge R, Mandelkow EM (2012) Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acty Neuropathol 123(6):787-805. doi: 10.1007/s00401-012-0987-3

Brouillette J, Caillierez R, Zommer N, Alves-Pires C, Benilova I, Blum D, De Strooper B, Buée L (2012) Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-beta1-42 oligomers are revealed in vivo by using a novel animal model. J Neurosci 32(23):7852-61. doi: 10.1523/JNEUROSCI.5901-11.2012

Krüger U, Wang Y, Kumar S, Mandelkow EM (2012) Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging 33(10):2291-305. doi: 10.1016/neurobiolaging.2011.11.009

Plucinska G, Paquet D, Hruscha A, Godinho H, Haass C, Schmid B, Misgeld T (2012) In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system. J Neurosci 32(46):16203-12. doi: 10.1523/JNEUROSCI.1327-12-2012

Van der Jeugd A, Blum D, Raison S, Eddarkaoui S, Buée L, D'Hooge R (2012) Observations in THY-Tau22 mice that resemble behavioural and psychological signs and symptoms of dementia. Behavl Brain Res 242C:34-9. doi: 10.1016/j.bbr.2012.12.008


Lo AC, Iscru E, Blum D, Tesseur I, Callaerts-Vegh Z, Buée L, De Strooper B, Balschun D, D’Hooge R (Jan 2013) Amyloid and Tau neuropathology differentially affect prefrontal synaptic plasticity and cognitive performance in mouse models of Alzheimer’s disease. J Alzheimers Dis 37(1):109-25. doi: 10.3233/JAD-122296

Burnouf S, Martire A, Derisbourg M, Laurent C, Belarbi K, Leboucher A, Fernandez-Gomez FJ, Troquier L, Eddarkaoui S, Grosjean ME, Demeyer D, Muhr-Tailleux A, Buisson A, Sergeant N, Hamdane M, Humez S, Popoli P, Buée L, Blum D (February 2013) NMDA receptor dysfunction contributes to impaired BDNF-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model. Aging Cell 12(1):11-23. doi: 10.1111/acel.12018

Ando K, Dourlen P, Sambo AV, Bretteville A, Bélarbi K, Vingtdeux V, Eddarkaoui S, Drobecq H, Ghestem A, Bégard S, Demey-Thomas E, Melnyk P, Smet C, Lippens G, Maurage CA, Caillet-Boudin ML, Verdier Y, Vinh J, Landrieu I, Galas MC, Blum D, Hamdane M, Sergeant N, Buée L (March 2013) Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker. Neurobiol Aging 34(3):757-69. doi: 10.1016/j.neurobiolaging.2012.08.004

Nuytens K, Gantois I, Stijnen P, Iscru E, Laeremans A, Serneels L, Van Eylen L, Liebhaber SA, Devriendt K, Balschun D, Arckens L, Creemers JW, D’Hooge R (March 2013) Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic plasticity in mice. Neurobiol Dis 51:144-51. doi: 10.1016/j.nbd.2012-11-004

Lécolle K, Bégard S, Caillerez R, Demeyer D, Grellier E, Loyens A, Csaba Z, Beauvillain JC, D’Halluin JC, Baroncini M, Lejeune JP, Sharif A, Prévot V, Dournaud P, Buée L, Colin M (March 2013) Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors. Gene Ther 20(3):283-97. doi: 10.1038/gt.2012.39

Messing L, Decker JM, Joseph M, Mandelkow E, Mandelkow EM (May 2013) Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors. Neurobiol Aging 34(5):1343-54. doi: 10.1016/j.neurobiolaging.2012.10.024

Blum D, Buée L (May 2013) Alzheimer’s disease risk, obesity and Tau: is insulin resistance guilty? Expert Rev Neurother 13(5):461-3. doi: 10.1586/ern.13.35

Caillerez R, Bégard S, Lécolle K, Deramecourt V, Zommer N, Dujardin S, Loyens A, Dufour N, Aurégan G, Winderickx J, Hantraye P, Déglon N, Buée L, Colin M (Jul 2013) Lentiviral delivery of the human wild-type Tau protein mediates a slow and progressive neurodegenerative Tau pathology in the rat brain. Mol Ther 21(7):1358-68. doi: 10.1038/mt.2013.66

Van der Jeugd A, Vermaercke B, Derisbourg M, Lo AC, Hamdane M, Blum D, Buée L, D’Hooge R (Epub) Progressive age-related cognitive decline in Tau mice. J Alheimers Dis ???. doi:10.3233/JAD-130110

Reinhard C, Borgers M, David G, De Strooper B (Epub) Soluble amyloid-beta precursor protein binds its cell surface receptor in a cooperative fashion with glypican and syndecan proteoglycans. J Cell Sci ???. doi: 10.1242/jcs.137919

Lo AC, Tesseur I, Scopes DI, Nerou E, Callaerts-Vegh Z, Vermaercke B, Treherne JM, De Strooper B, D’Hooge R (Epub) Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Abeta toxicity inhibitor SEN1500. Neuropharmacology. pii:S0028-3908(13)00397-3. doi: 10.1016/neuropharm.2013.08.030