PROJECTS SUPPORTED FOR 2005

Institut de Pharmacologie Moléculaire et Cellulaire – Valbonne

Role of aminopeptidase A in Aβ catabolism and function

Alzheimer’s disease is a neurodegenerative disease that is mainly associated with the over-production of a small peptide called amyloïd peptide or Ab. We all produce Ab and, in physiological conditions, this peptide remains at a low concentration where it remains soluble. For environmental or genetic reasons, this fragment is produced at a higher rate, accumulate and aggregate. It is thought that the aggregated form of Ab could be the toxic species partly responsible for Alzheimer’s disease pathology.

Ab also undergoes proteolysis, leading to Ab-related species that appear more toxic than the parent peptide. Several lines of evidence suggest that these fragments are the early deposited species in pathological brains and harbor exacerbated toxic properties.

Nothing is actually known concerning the mechanisms by which Ab could be cleaved and particularly the nature of the enzyme involved in the proteolysis of Ab. Furthermore, the function of Ab and its fragments is still unknown. Thus, several reports suggest that intact Ab could be toxic while others indicate that the peptide could be protective. The latter hypothesis would indirectly explain why Ab is physiologically produced.

Our project envision to delineate the nature of the enzyme generating N-terminally truncated fragments and the influence of this cleavage on the function of Ab, with special interest in the control of cell death.

November 1st,  2005 – October 31th, 2007

80 000€

INSERM, Université de Lille – Lille

Proteases generating the amino-truncated species of Ab

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 Aloïs 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 Alzheimer disease 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 origin 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 Ab peptide. Following our observations, we hypothesized that these pathologically-related truncated Ab 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 Ab peptides in inherited forms of AD and suggested to be more toxic and possibly responsible for the anticipation and aggressiveness of the disease. By a recent vaccination approach against some of these truncated Ab species, we evaluated our hypothesis, and established the early implication of truncated Ab for amyloid deposition and their specific relationship to AD.

However, the mechanism leading to these pathologic species of Ab is unknown. The aim of our project is to identify the proteases involved in their production. We will use a differential approach based on the characterization of various cellular conditions in regard of truncated Ab generation. The combination of transcriptomic, proteomic and enzymatic technics should permit the identification of the proteases responsible of the production of the earliest and the most pathologic species of truncated Ab. The newly charaterized “Ab-truncating” enzymes will be studied in a transgenic model known to produce large amounts of truncated Ab as early as 2 months and in sporadic AD brains. The validation of our results in human brain will allow the elucidation of the mechanism leading to the early and pathologic species of Ab.

Overall our project should give new insights in the understanding of the early events of AD as well as explore the possible diagnosis and therapeutic approaches associated to these therapeutic targets.

November 1st, 2005 – October 31th, 2007

80 000€