The low density lipoprotein receptor-related protein (LRP) is highly expressed in the brain and has been shown to alter the metabolism of amyloid precursor protein and amyloid- peptide (A) in vitro. Previously we developed mice that over-express a functional LRP minireceptor (mLRP2) in their brains and crossed them to the PDAPP mouse model of Alzheimer’s disease. Over-expression of mLRP2 in 22 month-old PDAPP mice with amyloid plaques increased a pool of carbonate-soluble A in the brain and worsened memory-related behavior. In the current study, we examined the effects of mLRP2 over-expression on 3 month-old PDAPP mice that had not yet developed amyloid plaques. We found significantly higher levels of membrane-associated A42 in the hippocampus of mice that over-expressed mLRP2. Using immunohistochemical methods, we observed significant intraneuronal A42 in the hippocampus and frontal cortex of PDAPP mice, which frequently co-localized with the lysosomal marker LAMP-1. Interestingly, PDAPP mice lacking apolipoprotein E (apoE) had much less intraneuronal A42. We also found that PC12 cells over-expressing mLRP2 cleared A42 and A40 more rapidly from media than PC12 cells transfected with the vector only. Pre-incubation of apoE3 or apoE4 with A42 increased the rate of A clearance and this effect was partially blocked by RAP. Our results support the hypothesis that LRP binds and endocytoses A42 both directly and via apoE, but that endocytosed A42 is not completely degraded and accumulates in intraneuronal lysosomes.