Amyloid fibrils are likely causative or contributing agents in diseases such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, and transmissible spongiform encephalopathies. AD represents a major health problem and heavy economic burden in industrialized countries. AD is characterized in pathology by the presence of several kinds of amyloid plaques in the brain patients. The main component of these plaques is the amyloid beta peptide (Ab). Because Ab is suspected to play a crucial role in AD, it represents an obvious therapeutic target. It is therefore, critical to understand the mechanisms by which Ab triggers a neurodegenerative cascade. Current evidence indicates that intraneuronal accumulation of Ab is an early pathological biomarker for the onset of AD. Interestingly, there are evidences showing that exogenous fibrillar Ab can lead to intracellular accumulation of endogenous Ab in cell culture. Recently, exogenous induction of cerebral Ab-amyloidogenesis by injection of amyloid-plaque-containing brain extracts in transgenic mice has been observed. These data are suggestive that exogenous fibrillar Ab are transmissible, by their ability to induce aggregation of endogenous Ab inside the cells. This hypothesizes a molecular mechanism similar to the propagation of the infective amyloid prion proteins. However, there are not yet studies evaluating this hypothesis. In the present application we propose to investigate through which molecular mechanism exogenous Ab aggregates may induces the aggregation of endogenous Ab, and to clarify the relevance of this process for the progression of the disease. For this purpose, we propose to determine whether endocytosed Ab aggregates may propagate their aggregation state to the endogenous Ab in neuronal cells. We propose also to investigate the effect of amyloid structure and metal binding of Ab peptides, the role of RAGE and thioredoxin anti-oxydant system, on Ab internalization and trafficking in neuronal cells.
Project partnersCentre National De La Recherche Scientifique Cnrs