Altered levels and distribution of IGF-II/M6P receptor and lysosomal enzymes in mutant APP and APP + PS1 transgenic mouse brains

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor participates in the trafficking of lysosomal enzymes from the trans-Golgi network or the cell surface to lysosomes. In Alzheimer's disease (AD) brains, marked up-regulation of the lysosomal system in vulnerable neuronal populations has been correlated with altered metabolic functions. To establish whether IGF-II/M6P receptors and lysosomal enzymes are altered in the brain of transgenic mice harboring different familial AD mutations, we measured the levels and distribution of the receptor and lysosomal enzymes cathepsins B and D in select brain regions of transgenic mice overexpressing either mutant presenilin 1 (PS1; PS1M146L+L286V), amyloid precursor protein (APP; APPKM670/671NL+V717F) or APP + PS1 (APPKM670/671NL+V717F + PS1M146L+L286V) transgenes. Our results revealed that levels and expression of the IGF-II/M6P receptor and lysosomal enzymes are increased in the hippocampus and frontal cortex of APP and APP + PS1, but not in PS1, transgenic mouse brains compared with wild-type controls. The changes were more prominent in APP + PS1 than in APP single transgenic mice. Additionally, all β-amyloid-containing neuritic plaques in the hippocampal and cortical regions of APP and APP + PS1 transgenic mice were immunopositive for both lysosomal enzymes, whereas only a subset of the plaques displayed IGF-II/M6P receptor immunoreactivity. These results suggest that up-regulation of the IGF-II/M6P receptor and lysosomal enzymes in neurons located in vulnerable regions reflects an altered functioning of the endosomal–lysosomal system which may be associated with the increased intracellular and/or extracellular Aβ deposits observed in APP and APP + PS1 transgenic mouse brains.