You can read the descriptions and results of each research project on Alzheimer’s disease funded by Fondation Vaincre Alzheimer.

Dr. Katharina Zimmermann

INSERM, Université Lille 2 – Lille

Degeneration of cholinergic neurons in tau pathology


The brains of Alzheimer’s disease (AD) patients contain two hallmark pathological features: senile plaques composed of deposits of amyloid-beta (Ab) peptide and neurofibrillary tangles (NFT) composed of tau protein. Aggregation of tau proteins into filaments is a common feature encountered in AD. Abnormal phosphorylation and hyperphosphorylation is the major modification of these aggregated proteins. Tau protein binds microtubules through microtubule-binding domains thereby maintaining dendritic stability and axonal transport. However, microtubule assembly depends partially upon the degree of phosphorylation since hyperphosphorylated tau proteins are less effective than hypophosphorylated Tau on microtubule polymerisation.

Recently, we developed a tau transgenic mouse model that shows tau hyperphosphorylation, abnormal tau phosphorylation, Gallyas positive NFT-like inclusions, paired haired filaments (PHF) like threads, ghost tangles, reduced basal synaptic transmission, hippocampal neurodegeneration, delayed learning and reduced memory, briefly an AD-like tau neuropathology.

Very interestingly, this model demonstrates a dysregulation of neurotrophic factors causing – according preliminary data – a cholinergic degeneration very similar to that found in AD brain. Today, the most striking symptom of AD, the loss of cholinergic synapses and neurons, have yet not been demonstrated in any APP or any tau transgenic model. For that reason, our mouse is very suitable to study the influence of tau pathology on cholinergic neurons in the basal forebrain.

Our main goal is to elucidate the mechanisms underlying the cholinergic degeneration in the basal forebrain of our novel transgenic mouse model.

Our objectives are to – quantify the loss of cholinergic neurons in the basal forebrain (e.g. basal nucleus of Meynert) of the tau transgenic mice

investigate the tau pathology (tau phosphorylation, NFT like inclusions and the occurrence of ghost tangles) in the basal forebrain of our mouse model

reveal the mechanisms of cell loss (necrosis/apoptosis/cell-cycle reentry) in the basal forebrain of tau transgenic mice

explore the involvement of reactive glia and their contribution to the cell death in the basal forebrain.

In conclusion, our research project is related to an early event of AD etiopathogenesis observed in familial and sporadic cases. Our study of cholinergic neuron degeneration will explore the possible therapeutic approaches associated to this very interesting therapeutic target.


Cholinergic neuron loss of the basal forebrain is a cardinal feature of Alzheimer disease. During a 15- to 20-year period of disease progression, a continuous loss of cholinergic neurons (50–87%) is observed in the basal nucleus of Meynert and in a number of cortical cholinergic synapses. Today, pharmacological treatment with cholinesterase inhibitors is the main treatment of AD patients. However, cholinesterase inhibitors can only delay the progression of the disease by a few years but do not maintain survival to cholinergic neurons. Improving our understanding of the mechanisms of cholinergic degeneration during pathogenic tau aggregation will help to elaborate a therapeutic strategy to specifically increase trophic supply and survival of cholinergic neurons in sporadic AD.

November 1st, 2006 – October 31th, 2007 (1 year)

20 000€

Dr. Thierry Pillot

Institut National Polytechnique de Lorraine, Lipidomix – Nancy

Functional validation of a therapeutic strategy for Alzheimer’s disease


Accumulative evidence emphasizes the key causative role of soluble oligomers of Aβ peptide (sAβ) in neuronal degeneration and early memory loss associated with early AD stages. Therefore, we presume that preventing sAβ toxic effects to neurons might represent a high priority in designing efficient neuroprotective approaches in the treatment of AD. Most of the strategies explored or under evaluation to date propose either to modulate Aβ generation or to increase Aβ clearance from the central nervous system. The project we present here relies on a distinct reasoning, considering that sAβ-induced neurodegeneration and associated synapse loss can be prevented by counteracting sAβ neurotoxic effects through the preservation of active survival (antiapoptotic) signaling pathways in neurons. Accordingly, we have recently observed that humanin (HN), an endogenous 24-aa peptide, protected cerebral cell models from sAβ in vitro, as well as sAβ-induced cognitive impairment in vivo.

Our main goal is to investigate the functional interest of delivering continuously humanin peptides in vivo, in order to prevent sAβ-induced neuronal damages as well as associated neurobehavioral injuries and cognitive impairments in AD mice models. To guaranty long-term administration as well as high local concentrations of HN peptide in particular brain structures including hippocampus, we have chosen to use recombinant cells stably expressing and secreting the therapeutic agent, followed by their encapsulation in alginate beads and selective implantation in mouse brain. In situ secretion of these factors from alginate-embedded cells should provide protection from sAβ-induced toxicity.

Our specific objectives are as follow:

1 – To optimize the implantation of alginate beads, containing recombinant cells designed to stably secrete humanin, in the brain of different mice models of AD (e.g. in AD Tg2576 mice and in stereotaxically sAβ-injected mice) – and to monitor humanin production and diffusion,

2 – To characterize the effects of humanin brain production on both cellular and tissular injuries associated with AD mice models, as well as on the cognitive performances of implanted mice.

While emphasizing the interest of in situ production of recombinant proteins in brain from cells encapsulated in transplanted alginate beads, this project will allow establishing the proof of concept that in situ-delivered humanin peptide exhibits neuroprotective capacities able to prevent sAβ-mediated synaptic loss and subsequent cognitive deficit. It is expected to lead to the development of a new therapeutic approach to prevent or to delay the burst of neuronal degeneration responsible for AD. By assessing the usefulness of these treatments in AD mice models exposed to sAβ, this project is expected to confirm the pertinence of the relevant pathways as pharma­cological targets in preventive therapies raised against AD. It should also functionally assess the interest of such neurosurgical approach for in situ delivery of other AD therapeutic proteins.


Accumulative evidence highlights the critical role played by soluble oligomers of the Aβ peptide in precocious stages of AD development. It is thus crucial to characterize, both in vitro and in vivo, the molecular mechanisms associated with soluble Aβ oligomer-induced neurodegenerative processes in order to identify cellular targets for soluble Aβ as well as factors able to prevent soluble Aβ-induced brain damage and subsequent cognitive impairment. Indeed, the development of therapeutic strategy to treat and/or prevent AD should take soluble Aβ oligomers into account.

In this context and based on our preliminary data, we proposed to make the proof of concept of a potential new therapeutic approach for AD based on continuous production of a neuroprotective factor in the brain of different mice models of AD. This will also allow us to determine whether such approach can be applied for in situ delivery of other therapeutic proteins already identified in our group.

November 1st, 2006 – October 31th, 2007 (1 year)

40 000€

Dr. Jean-Charles Lambert

INSERM, Institut Pasteur – Lille

Association of Collagen genes with Alzheimer’s disease ?


The genetic of the early-onset forms of Alzheimer’s disease (AD) begins to be well known conversely to that one of the late-onset forms, which appears to be highly more complex. Indeed, the number of genetic factors and the variability of their impact in these late-onset forms clearly complicate their identification. To date, the only recognized risk factor for these forms is the e4 allele of the apolipoprotein E (APOE) gene.

We have brought into the fore that functional polymorphisms within the APOE promoter are associated with an increased risk of developing AD. These data indicate that in addition to the qualitative effect of coding polymorphisms (such as the e4 one) on the AD occurrence, the quantitative variation of expression of a gene (for instance, due to promoter polymorphisms) contribute to the development of the disease. This observation have been extended to other genes implicated in AD such as PS1 and PS2 and for which variations in their expression in the brain of AD cases and controls have been observed. Altogether, these data suggest that the level and the control of expression of involved genes in the AD process may be a possibility of screening to research for new genetic determinants of AD.

From this working hypothesis, we developed a custom microarray in order to study the expression of all the ORFs (open reading frame) located within the chromosomal regions of interest defined by the genome scan studies. A bio-analysis work have been realised to finally keep 2741 ORFs located within 9 loci of interest. We selected for their quality, 12 AD and 12 control samples of total RNA extracted from post-mortem brain tissues and we performed transcriptomic experiments. After computational analysis, we finally identified 106 significantly differentially expressed genes. We already analysed the impact of the ornithine transcarbamylase gene and obtained promising results.

With this background, we propose to evaluate the role of single nucleotide polymorphisms (SNPs) and resulting haplotypes in 4 other highly differentially expressed and positional candidate genes (COL6A1, COL6A2, COL11A1 and COL11A2) with the risk of AD in a collaborative effort.

This project is built to use the state-of-art techniques to identify AD genes : (i) validation of the differential expression in AD brains compared with controls at both mRNA and protein levels; (ii) characterisation of SNPs associated with the risk of developing AD in several independent case-control studies, (ii) evaluation of the functionality of the SNPs yielding significant associations.


This project is designed for a better understanding of the pathological process of AD by the investigation of its genetic determinants. These genetic factors could be used as new pharmacological targets or be useful for diagnosis.


November 1st, 2006 – October 31th, 2007 (1 year)

39 625€