Over the last 10 years, numerous studies have indicated that the low-density lipoprotein receptor-related protein (LRP) may be important for the pathogenesis of Alzheimer's disease. These include studies showing that LRP can internalize membrane-bound forms of the amyloid precursor protein and cause increased Aβ production, and studies showing LRP can internalize Aβ bound to ApoE and α2-macroglobulin, causing increased Aβ clearance. One in vivo study that has been missing is the analysis of Aβ deposition in knockout LRP mouse models of AD. This study has not been possible, since LRP knockouts are not viable. However, Van Uden et al. took the interesting approach of studying mice that have the LRP-associated protein, RAP, knocked out. RAP is important for the maturation and trafficking of LRP, and RAP knockout mice have dramatically reduced levels of LRP. Van Uden et al. analyzed Aβ deposition RAP knockout mice crossed with APP transgenic mice. There were three possible outcomes to this study: no effect on Aβ, Aβ goes down, or Aβ goes up. The first outcome would probably not be...  Read more

Over the last 10 years, numerous studies have indicated that the low-density lipoprotein receptor-related protein (LRP) may be important for the pathogenesis of Alzheimer's disease. These include studies showing that LRP can internalize membrane-bound forms of the amyloid precursor protein and cause increased Aβ production, and studies showing LRP can internalize Aβ bound to ApoE and α2-macroglobulin, causing increased Aβ clearance. One in vivo study that has been missing is the analysis of Aβ deposition in knockout LRP mouse models of AD. This study has not been possible, since LRP knockouts are not viable. However, Van Uden et al. took the interesting approach of studying mice that have the LRP-associated protein, RAP, knocked out. RAP is important for the maturation and trafficking of LRP, and RAP knockout mice have dramatically reduced levels of LRP. Van Uden et al. analyzed Aβ deposition RAP knockout mice crossed with APP transgenic mice. There were three possible outcomes to this study: no effect on Aβ, Aβ goes down, or Aβ goes up. The first outcome would probably not be published. The second outcome (Aβ down) would support the hypothesis that LRP is more important for internalization of full-length APP, leading to production of Aβ. The third outcome (Aβ up) would support the hypothesis that LRP is more important for the clearance of Aβ. The results of Van Uden et al. support this last hypothesis. They found significantly more Aβ deposited in RAP knockout mouse brains at 10 and 18 months, and significantly higher amounts of Aβ42. The study was well controlled. The authors showed in RAP knockout mice, there were no changes in total APP levels, in the distribution of APP in the brain, in astrocyte activation, or in MAP2-positive dendrites. There was, however, the expected dramatic (80 percent) reduction in LRP levels. The authors point out that there was also a decrease in another receptor family member, the LDL receptor, and presumably in other family members. Thus, there is the possibility that other receptors besides LRP are responsible for the clearance of Aβ. But the main finding, that ApoE receptors act as a clearance mechanism for Aβ in the brain, is strongly supported.

View all comments by G. William Rebeck

Very good paper!

View all comments by liu qiang