Role of the low density lipoprotein receptor -related protein in the metabolism of the beta-amyloid precursor protein: Implications for Alzheimer's disease.

摘要

Alzheimer's disease (AD), is a multifactorial neurodegenerative disorder, responsible for most cases of senile dementia. An invariable hallmark of AD brains is the presence of insoluble protein aggregates, known as amyloid or senile plaques. The main proteic component of these plaques is a small, highly hydrophobic peptide termed beta- amyloid (Abeta). Abeta is generated by proteolytic processing of a much larger transmembrane protein named beta-amyloid precursor protein (APP). APP can undergo a non-amyloidogenic or an amyloidogenic processing pathway, the latter of which results in the generation of Abeta. Although the exact cellular compartment(s) in which Abeta is generated remains controversial, it has been shown that Abeta can be formed within endosomes, upon internalization of APP from the cell-surface. Alternative splicing of APP's mRNA originates three major isoforms, two of which (APPKPI) contain a Kunitz-type proteinase inhibitor domain. Previous studies have demonstrated that the multi-ligand endocytic receptor low density lipoprotein receptor-related protein (LRP) can mediate the endocytosis of both soluble and cell-surface APP KPI. On the other hand, genetic studies indicate that LRP, as well as two of its ligands (apolipoprotein-E and alpha2-macroglobulin), are associated with increased risk for late-onset AD.;The objective of this work was to elucidate the involvement of LRP in AD, by testing the following hypothesis: LRP-mediated internalization of cell-surface APP contributes to the amyloidogenic processing of APP, by facilitating its delivery to endosomal compartments, where Abeta can be generated.;Using two different experimental strategies, it was demonstrated that LRP does indeed modulate APP processing and Abeta generation. First, it was observed that long-term treatment of cells with an LRP antagonist reduced the amount of APP processed via the amyloidogenic pathway, and secondly, restoring LRP function to LRP-deficient cells resulted in a substantial increase in Abeta production.;In summary, these findings constitute the first biochemical evidence for the involvement of LRP in AD pathobiology, and indicate that the lack of normal LRP function correlates with a higher degree of non-amyloidogenic APP processing, while the presence of functional LRP favors the biosynthesis of Abeta.