|Art der Förderung:||Standard Projekt|
|Institution:||INSERM U422, Dept. of Cerebral Aging and Neurodegeneration|
|Projektleiter:||Dr. Nicolas Sergeant|
|Laufzeit:||01. November 2003 - 31. Oktober 2004|
Alzheimer’s disease (AD) is a devastating dementing disorder that affects a large proportion of elderly in the industrialized countries. Two typical lesions are observed in the brain: the neurofibrillary degenerating neurons and extraneuronal spherical deposits named amyloid deposits. Amyloid-beta (Ab) peptide is the component of amyloid deposits. It results for a complex degradation of a larger protein named APP for amyloid precursor protein.
The group of Dr. Nicolas Sergeant, INSERM U422, Lille, has concentrated its research on AD, as it is observed in the brain of the most represented noninherited form (99%). His observations have recently demonstrated that specific pathological modifications of Ab are likely seeding the amyloid deposition process. They thus represent a novel therapeutic target for a possible early treatment of AD.
Sergeant´s group aims at evaluating the therapeutic potentiality of those pathological products of Ab for a preventive vaccination approach. Vaccination leads to the clearance of a foreign or pathological body and has been shown to be an encouraging therapy against AD. However, many efforts as to be performed to further improve this therapeutic approach. The objective of Sergeant is thus to target the pathological products of Ab that are specifically related to AD. The vaccination project will be evaluate in a animal model that has been shown to produce the pathologic Ab products and amyloid deposition as in AD. Sergeant will demonstrate that the vaccination approach to be developed will be doubly beneficial first, by targeting pathological Ab that are not produced in normal individuals and second, because there are responsible for amyloid deposition in all form of AD. Thus vaccination could be used as a real preventive therapeutic approach because the risk of detrimental side effects are likely to be reduced by using a target that is only produced in AD.
Alzheimer's disease (AD) is a devastating dementing disorder that affects a large proportion of elderly in the industrialized countries. Since its first description by Alois Alzheimer at the beginning of the last century, two typical lesions are observed in the brain of individuals suffering of that disease. They consist of the intraneuronal accumulation of pathological fibrillar structures to form the neurofibrillary tangles and the extracellular formation of spherical deposits named amyloid deposits. In the mid eighties, the molecular history of AD has started consequently to the discovery of the proteins that constitute both lesions. Thus, abnormally modified microtubule-associated tau proteins are the basic components for neurofibrillary tangles whereas amyloid-beta (AB) peptide is the component of amyloid deposits. The latter results for a complex degradation of a larger protein named APP for amyloid precursor protein. In few families, AD is dominantly inherited and mutations on the APP gene have been discovered as well as mutation on presenilin, responsible for the most aggressiveness form of AD. Arising for the genetic form of AD and the development of animal models expressing the gene with the mutation the "Amyloid hypothesis" emerged to explain the aetiology of AD. In addition, diagnostic and therapeutic developments have been also driven following this hypothesis. However, more than 99% of patients affected by AD are isolated individuals and no genetic linkage has been established. This major form of AD named "sporadic" AD (SAD) is characterized by the presence of the same brain lesions and clinical development but the molecular events leading to SAD remain obscure. Our laboratory has concentrated his research on this most represented SAD form and developed multiple approaches to analyse and describe "the natural and molecular history of SAD"' More recently, by going deeper into the detailed and early molecular modifications observed in non-demented individuals with the typical lesions of AD, we have demonstrated for the first time that some specific modifications of AB characterize the early events of amyloid deposition in those individuals. These modifications consist of the truncation of one extremity of the Aβ peptide.
Following our observations, we hypothesized that these pathologically-related truncated Aβ peptides should have their importance in the aetiology of SAD. This hypothesis was further supported by the fact that previous scientific studies have observed the truncated Aβ peptides in inherited forms of AD and suggested to be more toxic and possibly responsible for the anticipation and aggressiveness of the disease.
Our project aims to evaluate our hypothesis that is the early implication of truncated Aβ for amyloid deposition and its specific relationship to AD. Vaccination has been shown to be an encouraging therapy against AD, even if detrimental side effects have lead to the arrest of the clinical trial. In both animal models of AD and in human vaccination against Aβ results in the clearance of the amyloid deposits. We use this methodology to vaccinate an animal model against the truncated Aβ, and only against truncated Aβ, and not against the naturally produce products. This is possible since we’ve recently characterized with the collaboration of a European company, Aventis-Pharma, an animal model that was closely reflecting what we observed in the human brain. This transgenic mouse model is making truncated Aβ and develops amyloid deposits. Thus our major objective is to determine the precise implication of the truncated Aβ using an animal model that is relevant to the human pathology.
Since the project has started, we designed peptides that lead to the production of specific antibodies against truncated Aβ in mice. The designed peptides were used as the vaccine in an animal model that, as we showed, reproduces the amyloid deposits observed in human.
During the two years we aim to demonstrate that truncated Aβ are the seeds for amyloid deposition in AD and that the vaccination approach we will develop be doubly beneficial first, by targeting truncated Aβ that are not produced in normal individuals and second, because there are responsible for amyloid deposition in all form of AD. Thus vaccination could be used as a real preventive therapeutic approach because the risk of detrimental side effects are likely to be reduced by using a target that is only produce with the development of AD. Overall our project should give new insights in the understanding of the early events of AD as well as potential improvement of the current therapeutic approaches developed against Alzheimer's disease. A long-term goal would be also to investigated the cellular mechanisms of production of the truncated Aβ species in cell models to design new drugs for additional treatment.