LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation.
The secreted form of beta-amyloid precursor protein (APP) containing the Kunitz proteinase inhibitor (KPI) domain, also called protease nexin II, is internalized and degraded by cells. We show that the low density lipoprotein (LDL) receptor-related protein (LRP) is responsible for the endocytosis of secreted APP. APPs770 degradation is inhibited by an LRP antagonist called the receptor-associated protein (RAP) and by LRP antibodies and is greatly diminished in fibroblasts genetically deficient in LRP. APPs695, which lacks the KPI domain, is a poor LRP ligand. Since LRP also binds apolipoprotein E (apoE)-enriched lipoproteins and inheritance of the epsilon 4 allele of the apoE gene is a risk factor for Alzheimer's disease (AD), these data link in a single metabolic pathway two molecules strongly implicated in the pathophysiology of AD.
Kounnas
M Z
MZ
Department of Biochemistry, Holland Laboratories, American Red Cross, Rockville, Maryland 20855, USA.
Moir
R D
RD
Rebeck
G W
GW
Bush
A I
AI
Argraves
W S
WS
Tanzi
R E
RE
Hyman
B T
BT
Strickland
D K
DK
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D007611:Aprotinin / Q000737:chemistry; D001665:Binding Sites; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004705:Endocytosis; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D007611:Aprotinin