PROJECTS SUPPORTED FOR 2013

Institut Pasteur de Lille – Lille

The BIN1-Tau neurotoxic link in Drosophila (Pilote)

SUMMARY OF PROPOSED RESEARCH

Using genome-wide association studies (GWAS), BIN1 was identified as the most important genetic risk gene for Alzheimer’s Disease (AD) after APOE. More recently, we demonstrated that BIN1-mediated genetic risk might be related to its ability to modulate Tau pathology. However, the molecular mechanism that links BIN1 to Tau toxicity remains unknown. Here I propose to use Drosophila to address this question in more detail. As a first hypothesis, Bin1 may regulate Tau conformation and phosphorylation, the main feature of aggregated Tau in AD, as we have shown that Tau and BIN1 interact directly. A deregulation of the actin cytoskeleton is a second good mechanism by which BIN1 and Tau could interact as abnormal bundling and accumulation of F-actin, similar to the actin-rich paracrystalline inclusions, known as Hirano bodies in Alzheimer’s Disease and other Tauopathies, mediates Tau-induced neuronal degeneration in Drosophila and as regulation of actin dynamics is conserved for BIN1 from yeast to human.

In this proposal we will: (1) establish the functional evolutionary conservation between human BIN1 and its Drosophila sequence homolog amphiphysin (amph) by rescuing the locomotor defects of amph null flies with the expression of the BIN1 isoforms; (2) assess differential effects of three representative BIN1/amph isoforms and functional domain mutants on Tau neurotoxicity. Two readouts, the eye roughness (GMR driver) and the survival of adult photoreceptor neurons (rh1 driver) will be used. An histological analysis in mosaic clone will also be performed ; (3) analyze the potential role of BIN1/amph on Tau phosphorylation. A set of Tau phosphorylation-specific antibodies will be tested in western blot. The effect of BIN1/amph isoforms on the toxicity of naïve human Tau, Tau[AP] phosphodeficient and Tau[E14] phosphomimetic mutant Tau will also be tested ; (4) analyze the role of actin dynamics in BIN1/amph-mediated Tau neurotoxicity. We will assess the levels of F-actin biochemically and on histological sections in amph null flies expressing Tau. We will test if BIN1-Tau interaction can be modulated by regulators of the actin cytoskeleton ; and (5) assess the interaction of BIN1/amph with other novel AD susceptibility factors with respect to Tau neurotoxicity.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

A major challenge in Alzheimer’s Disease research is to determine the molecular mechanism by which recently identified novel genetic risk loci affect Alzheimer’s Disease pathogenesis. The proposed research aims to understand how BIN1, the most important genetic risk gene for Alzheimer’s Disease after APOE , affects Alzheimer’s Disease risk. Interestingly, ongoing evidence in our lab indicates that BIN1 might act at the level of Tau, a central neurotoxic protein in Alzheimer’s Disease. The present proposal will use the fruit fly to understand the BIN1-Tau link in more detail. This research thus addresses a novel fundamental physiopathological pathway in Alzheimer’s Disease which is important to develop new therapeutic strategies that target the BIN1-Tau neurotoxic link.

January 1st, 2014 – December 31th, 2015 (2 years)

40 000€

CNRS – Bordeaux

Computer Modeling of Advanced Diffusion MRI for Micro-structural lesions detection in Alzheimer’s disease in Man and Animals Models (Pilote)

SUMMARY OF PROPOSED RESEARCH

Alzheimer’s disease is defined as the presence and the accumulation in the brain of microscopic structures, amyloid plaques (5-500 microns) and neurofibrillary tangles (1-10 microns). There is no non-invasive methods or radioactive tracers-free that allow to obtain in vivo information on these microstructures because of their microscopic size. However, advanced methods of diffusion MRI like q-space imaging (qSI) provide, properly analyzed, informations on the random movement of water on a scale of 2-20 microns. Our hypothesis is that the microscopic movement of water measured by qSI would provide information on the microscopic structures characteristic of Alzheimer’s disease. This hypothesis seems plausible since qSI and Diffusional Kurtois Imaging (DKI) (a more clinically-feasible qSI-derived method) have recently shown that randoms movements of water are significantly modified in areas of brain that are known to be affected by the disease. However, the exact relationship between the microstructural changes related to Alzheimer’s disease and markers of qSI is not known at present. Our project is therefore divided into two parts: one dedicated to image processing of qSI data acquired for Alzheimer’s diseased patients, the other being to acquire the same type of data in animal models of Alzheimer’s disease, associated with histologic confirmation of the presence of lesions. In retrospective, this project will establish in animal models (with progressive accumulation of mutations leading to the nearest complete animal model) how microscopic lesions of Alzheimer’s disease influences the random movement of water measured in vivo. This will therefore make strong assumptions about the nature of qSI signal measured in humans and its relationship with the characteristic lesions of the Alzheimer’s disease.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

Water average displacement measured with qSI in brain are in the 2-20 µm range. Consequently, qSI can probe theoretically the spatial scale defined by the size of amyloïds depositions (5-500 µm),accumulation of neurofibrillary tangles (1-10 µm) caused by tau proteins hyperphosphorylation or microtubule depolymerisation and thus we maked the hypothesis that qSI may be an efficient tool to probes Alzheimer’s disease specific microstructural hallmarks. This hypothesis is strongly sustained by the fact that qSI and DKI has been recently validated as efficient methods for Alzheimer’s disease diagnosis, showing qSI/DKI microstructural markers change in brain area like temporal lobe, where microscopic hallmarks of Alzheimer’s disease are known to be present at an early stage. Physics-based diffusion advanced method like qSI with accurate signal analysis would provide a potential diagnosis methodology that would benefit in the future of the increase of magnetic field gradients systems of clinical MRI scanners. As an “in-vivo histology” method, qSI application to Alzheimer’s disease and clinical practical implementations of theses methods like DKI may take importance for the early diagnosis and treatment of patients affected by Alzheimer’s disease. However, the validation of the hypothesis relating qSI/DKI markers and amyloïds/neurofibrillary tangles presence is needed before translation to clinical practice of these methods and is the aim of this current project.

January 1st, 2014 – December 31th, 2015 (2 years)

40 000€

INSERM – Lille

Do plant sterols protect against Alzheimer’s disease?

SUMMARY OF PROPOSED RESEARCH

1. Scientific background and general objective

Liver X receptors (LXRs) are nuclear receptors crucially involved in the regulation of cholesterol trafficking. We showed that pharmacological activation of LXRs improved cognitive performance in an animal model of Alzheimer’s Disease [1]. Plant sterols, cholesterol analogues derived from plants, are dietary derived LXRs agonists [2]. Recently, it was shown in an in vitro platelet model for Alzheimer’s Disease that plant sterols modify cholesterol induced amyloid-β (Aβ) release [3]. Synthetic LXR agonists yield contra-indicative side effects, such as hypertriglyceridemia which are not reported for plant sterol enriched diets. Therefore, we hypothesize that plant sterols are LXR dependent cognitive enhancers in Alzheimer’s Disease superior to synthetic LXR agonists.

1. Specific aims / Research questions

The aim of this study is to elucidate the potential of dietary plant sterols to modulate AD pathology.

1. Determine which plant sterols are the most potent LXR agonists, applying LXR reporter.
2. Elucidate the role of LXRs in plant sterol induced alterations in Amyloid Precursor Protein (APP) processing (in vitro).
3. Validate the influence of increased cerebral plant sterols on the Alzheimer’s Disease related cognitive impairment and molecular biological hallmarks in a well-established Alzheimer’s Disease animal model.
4. Rationale & methods

The research question is addressed via a bottom up approach.

1. Several plant sterols activate LXRs. In collaboration with the department of Botany (Chulalongkorn University, Bangkok, Thailand), an internal library of plant sterols is screened for LXR activation in a cell free and cell based assay. The LXR agonizing potential of the individual plant sterols, together with our recently described blood-brain barrier transfer rates [4], allows us to select the most relevant physiological LXR agonist(s).
2. Subsequently, we unravel the influence of the selected plant sterol(s) on Aβ generation. In a neuronal cell line, stably over-expressing APP, the APP production, processing and secretion as Aβ is quantified by ELISA, also after suppressing LXRα and/or LXRβ using siRNA or 22S-hydroxycholesterol. This experiment indicates whether plant sterol modulated APP processing is LXR dependent.
3. The APPswePS1ΔE9 mouse model is used to assess effects of plant sterols on the AD-related neuropathogenesis.
4. a) Firstly, APPswePS1ΔE9 mice will be cross-bred with ATP Binding Cassette (ABC) G5-knockout mice, to obtain a triple transgenic mouse model bearing high plant sterol levels in the brain throughout the development of the Alzheimer’s Disease pathology. Abcg5-ko mice display increased brain plant sterol levels, but do not display behavioral/cognitive changes [5]. Both animal models are at PI’s disposal.
5. b) Secondly, the in vitro selected plant sterols are orally administered to APPswePS1ΔE9 mice. Cognitive and biochemical outcome parameters reveal the potential of plant sterol enriched diets in the prevention and progression of Alzheimer’s Disease pathology.

Data from these studies pave the way for a translational add-on treatment in the emerging field of nutritional neuroscience.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

Brain cholesterol metabolism plays a central role in the development and progression of Alzheimer’s disease pathology. This challenging study is the first to elucidate whether plant sterols can be used for structural dietary application to provide an alternative for pharmacological LXR activators, which yield contra-indicative side effects such as hypertriglyceridemia. Besides the cognitive outcome measures, the influence of plant sterols on cellular APP processing, cleavage and secretion and cholesterol metabolism is elucidated. Since diet is an important environmental modulator in Alzheimer’s Disease, data from this study will pave the way for a translational add-on treatment in the emerging field of nutritional neuroscience.

January 1st, 2014 – December 31th, 2015 (2 years)

13 000€

Université Aix-Marseille – Marseille

Role of macrophage metalloelastase in neuroinflammation and neurovascular demise in Alzheimer’s Disease

SUMMARY OF PROPOSED RESEARCH

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of neurofibrillary tangles and amyloid plaque formation and involving blood brain barrier (BBB) dysfunction. Others and we have shown that matrix metalloproteinases (MMPs) contribute to neuroinflammation and neurodegeneration. MMPs can also process APP, degrade Aß and modulate properties of the BBB. Macrophage metalloelastase (MMP-12) is an inflammation-associated proteinase. Our preliminary data show that in 5xFAD transgenic mouse models of Alzheimer’s disease, MMP-12 expression is associated with the early signs of brain inflammation, that its activity is conspicuous in the BBB and glial cells at 6 months of age and is increased in the cerebrospinal fluid of Alzheimer’s Disease compared to non-AD patients. In vitro, MMP-12 is induced in inflamed BBB models and can cleave APP.

Hypothesis: MMP-12 is at the crossroads of APP/Aβ metabolism, neuroinflammation and BBB demise and may constitute a new early marker of Alzheimer’s Disease progression and/or a therapeutic target.
Global objective: in the spatio-temporal context of Alzheimer’s Disease, generate knowledge on the role of brain and vascular MMP-12 and evaluate whether MMP-12 is an early marker and/or therapeutic target in AD.

Specific aims:

Aim 1 – Study the expression, activity and role of MMP-12 during the progression of neuroinflammation and pathogenesis in the brains of mouse models of Alzheimer’s Disease

1.1 – Characterise the spatio-temporal expression and activity of MMP-12 in 5xFAD mice

1.2 – Study the interplay between MMP-12 expression/activity and inflammation in neural cells

1.3 – Study the interplay between MMP-12 expression/activity and APP/Aβ metabolism

Aim 2 – Study the interplay between MMP-12 expresssion/activity and inflammation in the BBB

Aim 3 – Evaluate in a novel 5xFAD/MMP-12^-/- bigenic strain we generated the role of MMP-12 in vivo and effects of its absence in Alzheimer’s Disease progression.

Methods: The project combines the expertise of a neurobiology laboratory specialized in the study of MMPs in brain pathology and a chemistry/biochemistry laboratory that developed unique molecular tools, activity probes and inhibitors to study MMP-12. The project is multidisciplinary, involving chemistry, biochemistry, pharmacology, molecular and cellular biology, cell imaging, and animal behavior approaches. In vitro studies on primary cultures of glial and neuronal cells and in vitro models of the BBB and in vivo studies on the 5xFAD, MMP-12^-/-, and bigenic 5xFAD/ MMP-12^-/- strains will address the role of MMP-12 in APP processing, neuroinflammation, BBB demise, animal behaviour and will determine whether MMP-12 is an early marker and/or therapeutic target in AD.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

There are no efficient therapeutic strategies to address the major medical, social end economical problems raised by the increasing number of Alzheimer’s Disease patients in the world. Also, early diagnostic markers that could allow implementation of prevention strategies to delay the progression of the disease are still lacking. MMP-12 has already been involved in inflammation and vascular disease, and in particular in atherosclerosis, and MMP-12 inhibitors have been shown to efficiently attenuate vascular inflammation in animal models. The relevance of the proposed project to Alzheimer’s disease and related dementia is the potential to better understand Alzheimer’s Disease pathogenesis and to propose novel diagnostic tools and/or therapeutic strategies that could delay the onset of the disease or slow disease progression, by acting in the brain parenchyma and/or the vascular system.

January 1st, 2014 – December 31th, 2015 (2 years)

80 000€

Centre Hospitalier Universitaire de Rouen – Rouen

Identification of small molecule therapeutics using Drosophila

SUMMARY OF PROPOSED RESEARCH

Despite numerous studies, the physiopathological mechanisms involved in Alzheimer’s disease and related dementia (e.g. Frontotemporal lobar degeneration (FTLD)) are still widely misunderstood, preventing rational design of therapeutic interventions that can halt or even reverse the progressive loss of neurological function. Currently available medications provide relatively small symptomatic benefit for some patients but neither prevent nor stop disease progression. Drug screening in vertebrates is extremely costly and of very low throughput. If this step remains crucial, it is strategically interesting to precede it by screenings in less sophisticated organisms combining genetic amenability, low cost and short lifetime compatible with large-scale screens. The power and usefulness of Drosophila have already been highlighted in the study of many neurodegenerative diseases. A major feature of neurodegenerative diseases is the progressive accumulation, in the brain of patients, of specific proteins in the form of inclusions (Aβ, Tau and TDP-43 in Alzheimer’s disease; or Tau, TDP-43 and FUS in FTLD). We have developed and characterized new transgenic Drosophila models, based on the expression of human Aβ, TDP-43 or FUS proteins that recapitulate several features of human disease, including early death. Expression of Aβ, TDP-43 or FUS proteins in adult differentiated neurons shortens the lifespan of the flies by 50, 60 and 70% respectively.

The goal of our project is to identify small molecule therapeutics for Azheimer’s disease and related dementias, using a Drosophila platform recently developed in our group. We will use fly survival as a phenotypic test. The longevity of a fly population provides a robust estimate of their general health and is a marker for quantifying the impact of age-related neurodegeneration. In this project, collections of small molecules will be tested for their efficacy to improve the longevity of Aβ, TDP-43 or FUS flies, and therefore to reduce Aβ, TDP-43 or FUS toxicities in vivo. Based on the post-translational modifications known to be specific to pathological proteins (abnormal phosphorylation and aggregation…), we will focus on compounds known to target kinases and phosphatases or to modulate aggregation. Depending on the progress of the project, for the hits identified, new analogs will be designed by chemist colleagues and evaluated in Drosophila to identify compounds with improved potency. Lastly, we will determine the molecular mechanisms affected by drug candidates in flies. The complete project should allow for the identification of new molecules of therapeutic interest and a better understanding of the pathophysiological mechanisms in Alzheimer’s disease and related dementias, using a powerful and economical tool for in vivo chemical screening.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) and Frontotemporal lobar degeneration (FTLD) are the two most common forms of presenile dementia, affecting more than 40 million people worldwide. As the population ages, Alzheimer’s Disease and related dementia will become a major social and public health problem. There is currently no cure for AD and related dementia. Available medications focus on managing symptoms, offer only relatively small symptomatic benefit for some patients, and do not prevent or stop disease progression. Interventions that could delay disease onset, slow disease progression (even modestly), or cure would have a major public health impact. Therefore, there is an unmet, critical need for novel drugs that prevent or ameliorate the molecular pathogenesis of Alzheimer’s Disease and related dementia.

January 1st, 2014 – December 31th, 2015 (2 years)

80 000€

CNRS – Valbonne

Sarco-Endoplasmic Reticulum Calcium ATPase 1 truncated protein in Alzheimer’s disease

SUMMARY OF PROPOSED RESEARCH

We aim to study the potential targeting of Endoplsmic Reticulum (ER) calcium (Ca²⁺) homeostasis as a mean to modulate Aβ production and synaptic and cognitive deficits in Alzheimer’s disease (AD) and to investigate the mechanisms underlying this regulation. We observed an increased expression of the C-terminally truncated variant of the sarco-endoplasmic reticulum Ca²⁺ ATPase1 (SERCA1), named S1T, in human brain Alzheimer samples as well as in different Alzheimer disease (AD) study models. Importantly, S1T function as an ER Ca²⁺ leak channel and its overexpression leads to ER stress and apoptosis. We will use both in vitro and in vivo Alzheimer’s Disease models, namely neuroblastoma cells overproducing toxic Amyloid β (Aβ) peptides and the 3xTg-AD mice (APPswe/PS1M146V/TauP301L) developed by Dr. La Ferla developing both senile plaques and tangle pathology in AD-relevant brain regions. Modulation of S1T protein level will be obtained using lentiviruses to overexpress or to repress S1T. We will study: 1- the interplay between S1T expression and Aβ in Alzheimer’s disease; 2- the role of S1T in AD-associated Ca²⁺ deregulation; 3- the impact of S1T in Amyloid Precursor Protein (APP) processing and the production of toxic Aβ peptides and the mechanisms underlying this phenomenon; 4- impact of S1T in vivo on Aβ load, synaptic deficit and cognitive decline.

For global and subcellular Ca²⁺ measurements, different approaches will be used namely recombinant Ca²⁺-based aequorin probes, FRET (Fluorescence resonance energy transfer)-based Ca²⁺ probes (cameleon) and fluorescent based probes (Fura2, AM). Analyses of processing of APP and accumulation of toxic forms of Aβ will be performed using western blot and immunohistochemestry techniques. Synaptic function will be investigated through the study of the expression of pre- and post-synaptic proteins, and the analyses of synapses and dendrites shape and density by using immunostaining techniques and imagery approaches. Assessment of cognition will be performed using standard behavior study techniques (fear conditioning, Morris water maze, and Novel object paradigm).

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

Alteration of the precisely regulated Ca²⁺ homeostasis is one of the known causes of neuronal malfunction and is observed long before the onset of the first symptoms of Alzheimer’s Disease. Thus targeting Ca²⁺ homeostasis may offer novel possibilities to reduce Aβ burden and to alleviate synaptic deficits and cognitive decline in Alzheimer’s Disease. This project will unravel the role of endoplasmic reticulum (ER) Ca²⁺ homeostasis in Alzheimer’s Disease. We expect to find that genetic or pharmacological modulation of S1T may critically influence the production of Aβ species, synaptic loss and downstream cognitive impairments in Alzheimer’s Disease. The obtained results may reveal new pathways implicated in the development and/or progression of Alzheimer’s Disease and pave the way for the development of new strategies for Alzheimer’s Disease therapy.

January 1st, 2014 – December 31th, 2015 (2 years)

80 000€

INSERM – Caen

Sleep disturbances and amyloid pathology

SUMMARY OF PROPOSED RESEARCH

Patients with Alzheimer’s disease (AD) exhibit both severe memory impairment and sleep disturbances, even in the predementia stages of the disease. Recent evidence, in mice models of Alzheimer’s Disease and in Humans, suggest that circadian dysregulation may exacerbate amyloid-beta (Aß) pathology at least in earliest stages. The proposed research aims at assessing how the quality of sleep, evaluated by means of self-reported questionnaires and polysomnography, influences brain Aß levels measured in vivo using both florbetapir-PET imaging and cerebro-spinal fluid (CSF) Aß level measurements.

For this purpose, 40 elderly controls and 30 patients with Mild Cognitive Impairment (MCI) will undergo a detailed neuropsychological evaluation and a sleep questionnaire developed in our laboratory to assess the subjective quality of sleep during three life periods (with one corresponding to the current time). Sleep will also be recorded at home using a portable polysomnography device to get an objective measurement of the quality of sleep during the examination period. Measurements will include sleep latency, sleep efficiency, the number and duration of awakenings, as well as the time spent in each sleep stage. Participants will also undergo a structural MRI scan, a florbetapir PET scan and a measurement of Aß levels in CSF. Main analyses will include: i) correlation analyses between sleep parameters and Aß measurements (from both PET images and CSF samples) to confirm and specify the links between both parameters; ii) comparisons of sleep parameters between individuals with high vs low amyloid deposition, and of Aß measurements between individuals with vs without sleep disturbances; iii) partial regression / mediation analyses to assess how sleep and Aß influence cognitive performances and establish the sequence of events; and iv) analyses of prediction of Aß or sleep follow-up parameters from Aß or sleep baseline parameters to establish the causal relationship between both factors. We expect that specific sleep disturbance parameters will be associated with greater cortical Aß deposition and/or CSF Aß levels in healthy elders and MCI patients and that mediation and longitudinal analyses will confirm the causal relationship between sleep quality and Aß level. This would in turn strongly support the idea that sleep quality influences Aß load, and should therefore be improved at least in at-risk populations.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

This research falls within the framework of studies aiming at identifying the factors that may exacerbate the neuropathological processes leading to Alzheimer’s disease. It focuses more precisely on sleep quality, assessing the impact of sleep disturbances on cognitive functions and Aß deposition, and aiming at determining which specific sleep parameters (and during which period of life) mostly influences the formation of amyloid plaques. The results will highlight the utmost importance of treating sleep disturbances in older adults – pharmacologically or not – and preserving sleep quality for optimal cognitive functioning but also to slow down the course of the degenerative process.

January 1st, 2014 – December 31th, 2015 (2 years)

80 000€

INSERM – Paris

Citrulline diet supplementation and APP cleavage

SUMMARY OF PROPOSED RESEARCH

Extracellular amyloid deposits are one of the two anatomico-pathological hallmarks of Alzheimer’s disease (AD). The main component of amyloid deposits is the amyloid peptide of 40-42 amino-acids (Aß) derived from a precursor protein (APP). The excess of Aß triggers a cascade of events such as neurotoxicity, oxidative damage that contribute to the progression of the disease. Any molecule able to decrease the cleavage into Aß peptide in absence of side effects would represent a potential of therapeutic applications in Alzheimer’s Disease. Based on recently published data and in our preliminary studies we propose to test the effect on APP cleavage of citrulline (CIT), an intermediary amino-acid linked to arginine metabolism, powerful anti-oxidant able to cross the brain blood barrier.

We previously observed that CIT supplemental diet in old rats for 3 months decreased the content of endogenous APP and APP-C99 fragment, first metabolite of Aß cleavage, in rafts comparatively to rats fed with a control food. We have repeated the experiment with the Alzheimer mouse model Tg2576 sacrificed/analyzed at 20 months of age and preliminary data show a significant decrease of amyloid deposits. Wild type animals under the same conditions have a decrease of endogenous APP-C99 fragment before APP decrease suggesting that CIT may act directly on beta secretase activity, probably by decreasing advanced glycation end products (AGEs) stimulating NK-kB pathway able to activate the beta secretase promoter. In addition, as we observed that 4-hydroxynonedal (4-HNE1) modified proteins are decreased in diet supplemented old rats, we shall investigate the anti-oxidant properties of CIT in Aß cleavage in vivo and in vitro on control neuroblastoma cell lines surexpressing sweAPP in absence or in presence of CIT in the conditioned medium for 24H. Consequently, Tg2576 mice fed for 14 and 17 months and sacrificed at 20 months of age and animals fed for 6 and 9 months and sacrificed at 12 months old will undergo behavior analyses, amyloid deposits, quantification of oligomers, beta and alpha secretase activity and their products. The APP metabolites will be checked in rafts and non rafts compartments. AGEs, Malondialdehyde plus (4-HNE1) will be studied in total cortex and hippocampus brain extracts. Amyloid metabolites and oxidative products will be studied also in sweAPP neuroblastoma cell lines. At least we shall check in vitro if CIT has an anti-aggregant activity on oligomers and fibrillar formation. These studies should bring informations for a potential use of CIT in a protective therapeutical approach.

RELEVANCE OF PROPOSED RESEARCH TO ALZHEIMER’S DISEASE

Citrulline increases muscle mass, muscle protein synthesis and muscle strength in old malnourished rats and corrects the effect of aging on body composition. Citrulline is given as diet supplementation on malnourished elderly population. If citrulline has an effect on amyloid cleavage in an Alzheimer mouse model and cognitive performances, this amino-acid could be used in the future as a nutritional preventive or maybe a curative therapy. Such application could be very rapid, as citrulline is already given to old people and has no known toxicity. In addition, it is known also that it crosses the blood brain barrier. Consequently, the absence of toxicity and the absence of problems to cross the blood brain barrier is an advantage on many other pharmacological molecules potentially efficient on some aspects of the pathology.

January 1st, 2014 – December 31th, 2015 (2 years)

80 000€