The EU-funded MEMOSAD project is in its final stage
Parts of the results have been presented at AD/PD 2011 in Barcelona
Four investigators from the MEMOSAD project receive the VERUM Award 2011
Munich, 15 March 2011 - A Pre-Conference Satellite Symposium of the 10th International AD/PD Conference 2011 in Barcelona, Spain, organized by the VERUM Foundation presented results from the EU-funded project MEMOSAD. MEMOSAD is a collaborative study on the molecular mechanisms of memory loss in Alzheimer’s disease (AD) and disease modifying therapeutics for the prevention of this memory loss. The study, carried out by ten European research groups and funded by the EU with € 3 millions, started in January 2008 and will run till June 2011. It is the first time that both the peptides Abeta and Tau, which have proven to play the decisive role in the pathogenesis of Alzheimer’s disease, are jointly dealt with in a major research project.
At the AD/PD 2011 Opening Ceremony under the presidency of Dr. Avraham Fisher, the VERUM Award 2011 was presented to four investigators in recognition of their outstanding scientific achievements. Voting by the MEMOSAD team leaders resulted in two first prizes of € 3.000 each awarded to Amantha Thathiah from Belgium and Chronis Fatouros from Germany, and two 3rd prizes of € 1.000 each that went to Marie-Christine Galas from France and Hans Zempel from Germany.
Amantha Thathiah, a post-doctoral fellow with a PhD in biochemistry at the Vlaams Instituut voor Biotechnologie (VIB) in Leuven, Belgium, received a 1st prize for her presentation “GPR3 modulation of the gamma-secretase complex and Abeta generation in Alzheimer’s disease”. The research group provided evidence that the genetic ablation of GPR3 in an AD mouse model leads to a dramatic decrease in Abeta peptide, the primary neuronal protein in the pathogenesis of AD, thus lowering the burden of amyloid plaques in the brain. In contrast, overexpression of GPR3 causes accumulation of Abeta. The diminished plaque burden is accompanied by an alleviation of the cognitive deficits in this mouse model. The study provides crucial mechanistic insight into the regulation of the gamma-secretase-mediated cleavage of the APP to Abeta by GPR3 and thereby indicates a potential therapeutic approach to modulate the gamma-secretase complex during AD progression.
Chronis Fatouros, a PhD student from the Institut für Biologie 3 at the Albert-Ludwigs-Universität in Freiburg, Germany, was awarded a further 1st prize for his presentation “A worm model of tauopathy”. Aggregation of Abeta and Tau are hallmarks of AD, whereby Abeta is considered toxic for neurons and Tau a downstream target. In a C.elegans models of Tau pathology expressing pro- or anti-aggregant Tau fragments the pro-aggregant transgenic lines showed an accelerated Tau pathology that was manifested by progressively impaired motility in young adult animals, neuronal defects such as axonal gaps and varicosities, and less pre-synaptic termini along the dorsal cord. The control lines expressing the anti-aggregant variants of Tau presented some mild defects of this kind only at older age. Compounds which can dissolve aggregated Tau in vitro lead to a significant improvement of the movement defect. By carrying out a genome-wide RNAi screen for suppressors of the motility defect some novel potentially interesting genes were detected whose knock-down alleviates Tau pathology were detected.
Marie-Christine Galas, a PhD and CNRS research associate at the J-P Aubert Research Centre, Inserm-Université Lille 2, France, was honoured for her presentation “Tau: more than a MAP” with a 3rd prize. The research group detected that Tau - mostly considered to be a cytosolic protein - can also be observed in the nucleus of neurons. Despite the dual localization in both cellular compartments, neither nucleo-cytoplasmic shuttle of Tau nor a function for the endogenous nuclear form of Tau has until now been described in neurons. Heat stress and oxidative stress induced a reversible accumulation of Tau in the nuclei of neurons and nuclear Tau was able to preserve the neuronal DNA integrity in stress condition. Based on these results, the new function of Tau seems to consist in the protection of nuclear DNA in neurons from stress induced damage that is supposed to contribute to the pathogenesis of AD. An attractive hypothesis would be that altered forms of Tau would fail to efficiently protect DNA from insults like oxidative stress that is indeed considered to be an early mechanism involved in AD etiopathology.
A further 3rd prize went to Hans Zempel, a PhD student at the Max-Planck-Unit for Structural Molecular Biology in Hamburg, Germany, for his presentation “Abeta oligomers cause local missorting of endogenous Tau into dendrites, Tau-phosphorylation, destruction of microtubules, and spines”. The research group found out that early changes of endogenous Tau induced by Abeta-oligomers in hippocampal neurons include missorting of endogenous Tau into soma and dendrites in a subset of neurons in contrast to the axonal sorting in normal neurons. Missorted dendrites show depletion of spines, elevated phosphorylation of Tau at several sites, and local elevation of some kinase activities. Missorting affects not only Tau, but also other axonal markers such as neurofilaments, and correlates with a dramatic local decrease of microtubules and mitochondria (~80%).The Abeta-induced effects on Tau missorting, depletion of microtubules and mitochondria, and loss of spines are prevented by the microtubule-stabilizer taxol, indicating that Abeta-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. The data suggest that Abeta oligomers induce changes in dendritic signalling pathways whose toxicity is amplified by Tau.
According to Prof. Franz Adlkofer of the Munich-based VERUM Foundation, the organizer and coordinator of the MEMOSAD project, the present situation in research on Alzheimer’s disease and related dementias may be summarised as follows:
“The societal and economic burden of neurodegenerative diseases is growing rapidly due to the increasing human life expectancy. Alzheimer’s disease is the most common form of dementia with a prevalence of around 1 % in western populations at age 65, rising to 25-35 % of those over 85. It is estimated that as many as 30 million people worldwide are already living with Alzheimer’s disease. By 2050, this figure may more than triple. If neither reliable tools for early diagnosis nor prevention or treatment options for Alzheimer’s disease are developed in the near future, a global pandemic exceeding even that of HIV/AIDS will be unavoidable. And worst of all (and shown again at the AD/PD Conference in Barcelona), Alzheimer’s disease plays hide-and-seek with researchers, because the most promising avenues today could be dead ends tomorrow. Faced with a social crisis of this dimension two different problems have to be seen and dealt with properly. 1) Compared to research in cancer and the diseases of heart and circulation not enough funds are available for research in neurodegenerative disorders by the EU and the European governments despite the foreseeable needs our societies will be confronted with in the foreseeable future. 2) Enough young and gifted scientists must be attracted into the extremely challenging and competitive area of research into neurodegenerative diseases. The VERUM Foundation wishes to support such a development by honouring outstanding scientific achievements of young scientists with an anticipated career in AD research.”
Based on the results obtained so far and partly presented at AD/PD 2011 in Barcelona, it can be stated that the EU-funded MEMOSAD project will turn out to be an extraordinarily successful research project!
Possible therapeutic targets have been identified and validated in various test systems:
- Gamma-secretase, a multiprotein complex consisting of Presenilin (PS), Aph1, Pen2, and Nicastrin (NCT), is responsible for the final cleavage of causing release of the Abeta peptide. The same activity cleaves Notch, N-Cadherin, and other important signalling molecules, which complicates the development of clinically useful inhibitors of gamma-secretase. The Aph1B subunit of gamma-secretase was identified as a candidate target to treat AD, since besides cleaving APP none of the other mechanisms may be involved (Partner 2).
- TUDCA is a bile acid found in liver, which possesses anti-apoptotic and neuroprotective properties. In APP/PS1 mice treated with TUDCA-supplemented food pellets for a period of 6 months memory rescue was observed when comparing treated versus non-treated transgenic mice. A significant decrease in Abeta plaques in both hippocampus and cortex was observed in treated transgenic mice. Moreover, no difference between treated transgenic and control WT mice could be detected (Partner 9).
- Tau accumulation and aggregation is cleared mainly by the process of macroautophagy. Therefore, it was investigated whether trehalose, a non-reducing disaccharide which has been reported to enhance autophagy, is suitable for therapeutic intervention. Autophagy was indeed activated in the regulatable tau-expressing N2a cell system and concomitantly a reduction in Tau levels and toxicity was observed. The effects of trehalose are currently under investigation with the regulatable Tau-transgenic mouse model (Partner 3)
- Toxic effects of Tau are largely eliminated in mice with the human tau gene when this gene is switched off. After the deactivation of the tau gene the mice which previously demonstrated symptoms of dementia regain their ability to learn and remember and the synapses of the neurons reappear at least in part. At present compounds are tested that may prevent the formation of Tau deposits in the mouse model (Partners 3 and 9)
- The CREB pathway plays an important role in Abeta- and tau-mediated toxic effects. It was shown in neurons of the APP J9 mice that Abeta caused a dysfunction of CREB coactivators such as CBP, p300, TORC1 or TORC2 – rather than CREB itself. Adenoviral-mediated gene transfer that increased the TORC1 levels in the hippocampus recovers cognitive function in APP J9 mice (Partner 8).
- After a long-lasting exercise period, Thy-Tau22 mice displayed significant memory improvement in the Y-maze spatial memory task as compared to Thy-Tau22 mice without running wheels. Memory improvement was accompanied by a strong increase in hippocampal BDNF levels, supporting a substantial role of this neurotrophic factor in the observed effects (Partners 4 and 9).
- Active Tau immunization targeting a particular Tau epitope (ser422) in the Thy-Tu22 mouse model was carried out (i) to validate Tau phosphorylation as a candidate for therapeutic target and (ii) to investigate the efficacy of a therapeutic vaccine. A specific immune response was obtained against the targeted epitope. Biochemical analyses showed a decrease of the aggregated Tau in vaccinated Thy-tau22 mice and, importantly, active immunotherapy delayed cognitive deficits in the animals as observed in the Y-maze test (Partners 4 and 9).
These are possible therapeutic strategies which can be delineated from the results obtained so far:
Anti-Abeta-aggregation compounds were provided by Participant 10 and anti-tau-aggregation compounds by Participant 3. There are already promising results for several of these compounds, which are at present tested and further evaluated for their efficacy in the in vitro-systems and animal models available within the MEMOSAD consortium. An immunotherapeutical attempt applying an anti-tau-antibody in Thy-Tau22 mice is ongoing in the lab of Partner 4. Combining first results from this work with the tau-gene-knockout-results obtained in the lab of Partner 3 supports the view that a breakthrough in the treatment of AD is not only feasible, but may be reached in the not too far future.
MEMOSAD Pre-Conference Symposium