TGFβ2-induced changes in LRP-1/TβR-V and the impact on lysosomal Aβ uptake and neurotoxicity

Abstract

Numerous studies suggest a central role for the low-density lipoprotein receptor-related protein/transforming growth factor beta receptor V in Alzheimer's Disease. We continue our investigation of a ligand for this receptor, transforming growth factor beta2, which is also implicated in Alzheimer Disease pathogenesis, but whose mechanism(s) remain elusive. Confocal imaging reveals that transforming growth factor beta2 rapidly targets amyloid beta peptide to the lysosomal compartment in cortical neurons and induces cell death. Low-density lipoprotein receptor-related protein/transforming growth factor beta receptor V is known as an endocytic receptor, delivering proteins to the lysosomal compartment for degradation. Transforming growth factor beta2 may alter this pathway resulting in increased uptake, intracellular accumulation and toxicity of amyloid beta peptide. RT-PCR and Western blot analysis of transforming growth factor beta2-treated cells demonstrate that transforming growth factor beta2 modestly increases the mRNA and protein levels of low-density lipoprotein receptor-related protein/transforming growth factor beta receptor V as well as increases the uptake activity. Furthermore, transforming growth factor beta2 alters the morphology and numbers of lysosomes in neurons. Lucifer Yellow and lysosomal hydrolase analysis show that transforming growth factor beta2 makes lysosomal membranes unstable and leaky and this effect is exacerbated with the addition of amyloid beta protein. Our data support a key role for low-density lipoprotein receptor-related protein/transforming growth factor beta receptor V in mediating transforming growth factor beta2 enhancement of amyloid beta peptide uptake and neurotoxicity.