PROJECTS SUPPORTED FOR 2016
You can read the descriptions and results of each research project on Alzheimer’s disease funded by Fondation Vaincre Alzheimer.
Dr Guillaume Dorothée
CRSA, INSERM, CHU Saint-Antoine, Université Paris 6
Role and therapeutic potential of regulatory T cells in Tauopathy
PROJECT SUMMARY
Our studies in a mouse model of Tauopathy (THY-Tau22) suggest that Tau pathology drives the development of conventional T cell responses that promote disease progression. Regulatory T cells (Tregs) are particular T cells with the unique capacity to inhibit conventional T cell responses. Our data raise the hypothesis that Tregs play a key role in controlling Tau-driven T-cell-mediated detrimental processes in AD. Based on Treg-specific depletion and amplification studies in a mouse model, our specific aims are to 1) characterize the impact of Tregs on the progression of Tau-related pathophysiology, 2) evaluate the therapeutic potential of a Treg-based immunomodulatory approach in Tauopathies.
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
Besides innate neuroinflammation, recent data emphasize a role of adaptive immunity and particularly T cell responses in the pathophysiology of AD. However, the impact on disease progression of T cell responses to various pathological deposits involved in AD is poorly defined. Whereas previous reports suggest that different anti-Aβ T cell populations could be either detrimental or beneficial, much less is known regarding anti-Tau T cell responses and their regulation. Our study will lead to better understand the role of adaptive immunity and Tregs in Tau-related pathology, and may provide a proof of principle for the efficacy of innovative Treg-based immunotherapy approaches in Tauopathies.
January 1st, 2017 – December 31th, 2018 (2 years)
100 000 €
Prof. Chiara Zurzolo
Institut Pasteur, CNRS, Paris
Mechanisms involved in tau intercellular spreading
PROJECT SUMMARY
Tauopathies including Alzheimer’s diseases (AD), are characterized by the aggregation of tau protein. Evidences suggest that disease progression is associated to the spreading of aggregated tau in the brain. The mechanism responsible for tau intercellular transfer is still unclear. Our preliminary evidence suggests that tunneling nanotubes (TNTs), membranous connections allowing direct communication between distant cells, might play an important role in the propagation of tau. Here, we propose to study the intercellular spreading of tau in primary neurons and brain slices. This work will allow a better understanding of AD progression.
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
Although the evidences supporting prion-like seeding and propagation of tau pathology are very strong, the mechanism(s) by which tau transfers from cell-to-cell is not very well uderstood yet. A deeper understanding of tau aggregates self-perpetuating nature and the spreading mechanisms between cell compartments, cells, and brain regions is important to understand AD pathogenesis, to identify possible new therapeutic targets and to design therapeutic strategies to halt disease progression.
January 1st, 2017 – December 31th, 2018 (2 years)
100 000 €
Dr Hélène Marie
IPMC, CNRS, Université de Nice Sophia Antipolis, Valbonne
Design of antagonistic aptamers to block endogenous function of Aeta and Abeta
PROJECT SUMMARY
The well-known Amyloid-beta (Ab) and the newly-discovered A-eta, both APP-cleaved peptides, display strong bioactivities by altering synapse function.Developing specific antagonists to prevent their neurotoxic actions in vivo would be highly valuable for Alzheimer’s disease (AD) research. We propose to create aptamers, small oligonucleotide probes, which prevent the peptides’ actions on synapses. We here provide a proof of concept of our innovative approach by reporting that a published aptamer can, albeit at high doses, prevent Ab’s effects on NMDA receptor currents. We will screen and validate (biochemistry, electrophysiology) new antagonistic aptamers against these two peptides.
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
The endogenous action of Ab and Aeta are still largely unknown. Also, most current compounds designed to clear brain Ab failed to provide real clinical benefits. There is thus a strong need to create innovative research and therapeutic compounds, including to completely new targets such as Aeta. These new antagonistic aptamers fit perfectly in this context. In pre-clinical research, they will be useful to investigate peptides’ endogenous actions in the healthy brain and will be tested for therapeutic benefits in AD disease models. In due course, they could be optimized for ex-vivo use as a new type of biomarker and for in vivo use to specifically block Ab and Aeta synaptotoxic actions.
January 1st, 2017 – December 31th, 2018 (2 years)
100 000 €
Dr Uwe Maskos
Institut Pasteur, CNRS, Université Paris 6
Role of the nicotinic receptor(s) in Alzheimer’s Disease pathology and treatment
PROJECT SUMMARY
Nicotinic acetylcholine receptors (nAChRs) are targets of the amyloid beta (Ab) peptide, as demonstrated in vitro.
Here, we want to establish the role(s) of different nAChR subunits, alpha7 and beta2, in their contribution to AD pathology, or protection, and establish the role(s) of nAChR agonists and antagonists to halt the progression of the disease and improve cognition in subjects. We will continue to dissect our first observations that the lack of the beta2 subunit in the hippocampus protects mouse models from Ab induced memory deficits, using in vivo two-photon imaging and behavioural and pharmacological approaches.
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
The first group of cells to degenerate in AD are cholinergic neurons. This deficit in acetylcholine can be restored for some time in patients with acetylcholine esterase inhibitors. Acetylcholine activates nicotinic acetylcholine receptors (nAChRs). nAChRs themselves are targets of the amyloid beta (Ab) peptide, as demonstrated extensively in vitro. When crossing AD mouse models with a knock-out of the alpha7 subunit of the nAChR, two US groups obtained conflicting results, the first found improved cognition in the mice, the second increased signs of neuropathology. Here, we want to further our understanding of the role of nAChRs, and demonstrate that their role is crucial on interneurons.
January 1st, 2017 – December 31th, 2018 (2 years)
100 000 €
Dr Claire Meissirel
CRNL, Inserm, CNRS, University Lyon 1
Impact of VEGF on synaptic and cognitive dysfunction in Alzheimer disease
PROJECT SUMMARY
We recently demonstrated that the Vascular Endothelial Growth Factor (VEGF) facilitates hippocampal synaptic plasticity and memory in mice through signaling in neurons. Thus, VEGF is a promising candidate for treatment of synaptic and cognitive deficits in Alzheimer disease (AD). Our aim is to investigate how VEGF which accumulates in senile plaques might counteract Aβ synaptotoxicity in models of AD. Specifically we will :
1 Characterize VEGF impact on Aβ-mediated impairments in synapse structure and function.
2 Investigate VEGF and VEGFR2 expression patterns in AD postmortem human and murine brains
3 Identify Aβ-VEGF binding interactions and study in vivo consequences of their disruption
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
AD teatment targeting production or accumulation of toxic proteins have provided insufficient benefits. A current challenge is to increase neuronal resistance to Aβ-mediated synaptic toxicity that characterizes the early phases of AD. We recently showed that VEGF signaling is a key pathway involved in synaptic strenghthening and cognitive memory processes .The proposed study will examine the impact of VEGF signaling and underlying molecular mechanisms on resistance to the alteration of synapses in AD.
January 1st, 2017 – December 31th, 2018 (2 years)
100 000 €
Dr Maria Magiera
Institut Curie, CNRS, Université Paris Sud, Orsay
The role of the ‘tubulin code’ in Alzheimer’s disease
PROJECT SUMMARY
We propose to investigate the role of the “tubulin code” in the pathogenesis of the Alzheimer disease (AD). We have shown that disturbing polyglutamylation, one of the components of the “tubulin code”, leads to neurodegeneration in mice. We thus hypothesise that perturbations of this code could be involved in the pathogenesis of AD. Here we will analyse the status of polyglutamylation in the human AD samples by immunological methods, and the expression levels of the modifying enzymes by quantitative PCR. We will further investigate the mechanism by which polyglutamylation leads to neurodegeneration by analysing neuronal transport mechanisms in mouse neurons.
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
Growing evidence points to dysfunctions of the microtubule (MT) cytoskeleton in the pathogenesis of Alzheimer’s disease (AD). While many studies focused on the dysfunction of MT-associated proteins (MAPs) and motors, the implication of the MTs themselves has rarely been addressed. MTs are subjected to a number of posttranslational modifications (PTMs), which generate a ‘tubulin code’. This code can regulate neuronal MTs, and in particular their interactions with MAPs and motors. A disturbed ‘tubulin code’ in neurons could thus be the source of many of the MT-related dysfunctions (e.g. axonal transport defects, MAP aggregation) in AD and other neurodegenerative disorders.
January 1st, 2017 – December 31th, 2018 (2 years)
40 000 €
Dr Valérie Vingtdeux
JPArc, Inserm, Université Lille 2, CHU Lille
Role of AMP-activated protein kinase deregulation in Alzheimer’s disease
PROJECT SUMMARY
Alzheimer’s disease (AD) is characterized by early metabolic alterations and synaptic loss which origins remain poorly understood. Interestingly, deregulation of the metabolic sensor and regulator AMP-activated protein kinase (AMPK) have been described in the brain of AD patients. Here, our goal is to determine whether AMPK deregulation leads to metabolic alterations eventually leading to synaptic loss. Being also involved in the clearance of amyloid-beta peptide and tau phosphorylation, AMPK could therefore be a central player in the development of AD pathology.
RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE
Overall, the realization of our project should demonstrate that AMPK over-activation is an early upstream player in AD development. Our project should strengthen the notion that AD should be regarded as a brain metabolic disorder and eventually bring forward original alternative hypothesis for therapeutic strategies that are still desperately needed. Finally, AMPK is becoming a choice therapeutic target in current clinical trials for type II diabetes with molecules aiming at activating the kinase. In this context, our preliminary results suggest that some caution should be taken and implicate that a better knowledge of the mechanisms regulated by central AMPK over-activation is required.
January 1st, 2017 – December 31th, 2018 (2 years)
