It’s a RAP—Loss of LRP Increases Amyloid Deposition in Mice

The low-density lipoprotein receptor-related protein, or LRP for short, is part of a family of receptors that mediate the uptake and destruction of extracellular molecules including apolipoprotein E. Previous in vitro experiments have shown that amyloidβ (Aβ) is a ligand for LRP, suggesting that the receptor may play a role in the dynamics of amyloid plaque formation and in the etiology of Alzheimer's disease. In today's Journal of Neuroscience, researchers in Eliezer Masliah's lab at the University of California, San Diego, report that mice deficient in the receptor have elevated deposition of Aβ and a concomitant increase in neurodegeneration.

First author Emily van Uden and colleagues generated transgenic mice that expressed human AβPP but were deficient in LRP, by crossing hAβPP mice with receptor-associated protein (RAP) knockout mice. Loss of RAP, a chaperone, has previously been shown to result in low levels of LRP and other lipoprotein receptors, and this strategy circumvents a major obstacle to analyzing LRP null mice, namely lethality.

RAP-negative offspring had 20 percent residual LRP levels while maintaining their expression of hAβPP. Their Aβ deposition was almost doubled in both the hippocampus and frontal cortex, and they also had substantially more neurodegeneration as estimated by the loss of the dendritic marker MAP2.

The results seem to support the earlier in vitro data suggesting that loss of LRP may have profound effects on Aβ movements. However, as the authors explain, RAP is also important for trafficking of other receptors, such as low density lipoprotein receptor and apolipoprotein E receptor 2. While these proteins are not affected to the same extent as LRP in the RAP null animals, they may contribute to the phenotype. It is worth noting that levels of LRP have been shown to decrease with age and that a polymorphism in the gene for the receptor has been linked to late onset AD (Kang et al., 1997).—Tom Fagan

Comments

  1. 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

  2. Very good paper!

    View all comments by liu qiang

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References

Paper Citations

  1. Kang DE, Saitoh T, Chen X, Xia Y, Masliah E, Hansen LA, Thomas RG, Thal LJ, Katzman R. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology. 1997 Jul;49(1):56-61. PubMed.

Further Reading

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Primary Papers

  1. Van Uden E, Mallory M, Veinbergs I, Alford M, Rockenstein E, Masliah E. Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein. J Neurosci. 2002 Nov 1;22(21):9298-304. PubMed.

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