Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Aβ42 accumulation in amyloid model mice

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-beta peptide (A beta) in vitro. Previously we developed mice that overexpress a functional LRP minireceptor (mLRP2) in their brains and crossed them to the PDAPP mouse model of Alzheimer disease. Overexpression of mLRP2 in 22-month-old PDAPP mice with amyloid plaques increased a pool of carbonate-soluble A beta in the brain and worsened memory-related behavior. In the current study, we examined the effects of mLRP2 overexpression on 3-month-old PDAPP mice that had not yet developed amyloid plaques. We found significantly higher levels of membrane-associated A beta 42 in the hippocampus of mice that overexpressed mLRP2. Using immunohistochemical methods, we observed significant intraneuronal A beta 42 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 A beta 42. We also found that PC12 cells overexpressing mLRP2 cleared A beta 42 and A beta 40 more rapidly from media than PC12 cells transfected with the vector only. Preincubation of apoE3 or apoE4 with A beta 42 increased the rate of A beta clearance, and this effect was partially blocked by receptor- associated protein. Our results support the hypothesis that LRP binds and endocytoses A beta 42 both directly and via apoE but that endocytosed A beta 42 is not completely degraded and accumulates in intraneuronal lysosomes.