Receptor-associated protein (RAP) plays a central role in modulating Abeta deposition in APP/PS1 transgenic mice.
BACKGROUND
Receptor associated protein (RAP) functions in the endoplasmic reticulum (ER) to assist in the maturation of several membrane receptor proteins, including low density lipoprotein receptor-related protein (LRP) and lipoprotein receptor 11 (SorLA/LR11). Previous studies in cell and mouse model systems have demonstrated that these proteins play roles in the metabolism of the amyloid precursor protein (APP), including processes involved in the generation, catabolism and deposition of beta-amyloid (Abeta) peptides.


RESULTS
Mice transgenic for mutant APPswe and mutant presenilin 1 (PS1dE9) were mated to mice with homozygous deletion of RAP. Unexpectedly, mice that were homozygous null for RAP and transgenic for APPswe/PS1dE9 showed high post-natal mortality, necessitating a shift in focus to examine the levels of amyloid deposition in APPswe/PS1dE9 that were hemizygous null for RAP. Immunoblot analysis confirmed 50% reductions in the levels of RAP with modest reductions in the levels of proteins dependent upon RAP for maturation [LRP trend towards a 20% reduction ; SorLA/LR11 statistically significant 15% reduction (p<0.05)]. Changes in the levels of these proteins in the brains of [APPswe/PS1dE9](+/-)/RAP(+/-) mice correlated with 30-40% increases in amyloid deposition by 9 months of age.


CONCLUSIONS
Partial reductions in the ER chaperone RAP enhance amyloid deposition in the APPswe/PS1dE9 model of Alzheimer amyloidosis. Partial reductions in RAP also affect the maturation of LRP and SorLA/LR11, which are each involved in several different aspects of APP processing and Abeta catabolism. Together, these findings suggest a central role for RAP in Alzheimer amyloidogenesis.
Xu
Guilian
G
Department of Neuroscience, McKnight Brain Institute, Santa Fe Health Alzheimer's Disease Research Center, University of Florida, Gainesville, Florida, United States of America.
Karch
Celeste
C
Li
Ning
N
Lin
Nianwei
N
Fromholt
David
D
Gonzales
Victoria
V
Borchelt
David R
DR
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017353:Gene Deletion; D006720:Homozygote; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism / Q000502:physiology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics*; D018110:Receptors, Lipoprotein / Q000737:chemistry
D016229:Amyloid beta-Peptides; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D053764:Presenilin-1; D018110:Receptors, Lipoprotein
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