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
- 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.
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- 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.