Modulators of AbetaPP processing and their role in Alzheimer's disease pathogenesis

Abstract

Aberrant processing of the Amyloid-beta Protein Precursor (AbetaPP) is regarded as a critical event in the pathogenesis of Alzheimer's disease (AD) for two main sets of reasons: first of all the cytotoxic Abeta peptide, whose accumulation in extracellular plaques in the brain is a pathological hallmark of AD, derives from AbetaPP upon two sequential proteolytic events. Additionally, most autosomal dominant forms of early onset AD are caused by mutations in one of three genes: Presenilin-1 (PS-1), Presenilin-2 (PS-2) and AbetaPP itself. PS-1 and PS-2 are components of a multimolecular enzymatic complex with proteolytic activity called gamma-secretase, which is responsible for the characteristic intramembrane cleavage of several transmembrane proteins, among which is AbetaPP. In general, all the mutations associated with hereditary forms of AD cause an increase in Abeta production, especially in its most cytotoxic variant of 42 amino acids. AbetaPP processing has gained even more importance in recent years, upon the discovery that the AbetaPP Intracellular Domain (AID), released by the same proteolytic events that generate Abeta, can play several roles in signal transduction and that its overproduction might also be implicated in the onset of AD.;The purpose of this thesis work was to identify and characterize factors involved in the modulation of AbetaPP processing. Two main projects have been pursued: the characterization of potential cell surface ligands for AbetaPP and the cloning and description of a novel protein (named AID Associated protein 1 or AIDA-1) interacting with the AbetaPP Intracellular Domain.;Our results suggest that AbetaPP ligands actually exist and are expressed on the cell surface of most cell lines. Moreover, we have demonstrated that some of these molecules are attached to the cell membrane through a glycosyl-phosphatidylinositol (GPI) anchor and we have set up a system by which these potential ligands can be purified.;Additionally we have cloned and characterized several isoforms of AIDA-1 and we have demonstrated that this protein interacts with AbetaPP in an isoform specific manner: in fact, alternative splicing of a specific region of the AIDA-1 protein modulates its binding to AbetaPP. We have also demonstrated that over-expression of AIDA-1a causes a reduction in Abeta secretion, providing a potential mechanism for processing modulation.;Identifying the molecules responsible for the modulation of AbetaPP processing and understanding the mechanisms at its basis are fundamental steps towards the characterization of novel and effective drug targets to prevent and/or cure Alzheimer's disease.