A 3'-UTR polymorphism in the oxidized LDL receptor 1 gene increases Abeta40 load as cerebral amyloid angiopathy in Alzheimer's disease.
It is presently unclear whether polymorphic variations in the oxidized low-density lipoprotein receptor 1 (OLR1), or low-density lipoprotein receptor-related protein 1 (LRP1), genes act as risk factors for Alzheimer's disease (AD). In the present study, we have investigated the extent of amyloid beta protein (Abeta) deposition as cerebral amyloid angiopathy (CAA) or senile plaques (SP) in relationship to OLR1 +1071 and +1073 polymorphisms and LRP1 C766T polymorphism in patients with AD There was an increased Abeta40 load as CAA, but not as SP, in frontal cortex of AD patients carrying OLR1+1073 CC genotype, compared to those with CT, TT or CT+TT genotypes, but only in those individuals without apolipoprotein (APOE) epsilon4 allele. No differences in total Abeta or Abeta42 load as CAA or SP between OLR1+1073 genotypes was seen, nor were there any differences between OLR1+1071 and LRP1 genotypes for any measure of Abeta. Present data suggests that homozygosity for the C allele for OLR1+1073 polymorphism, selectively in individuals without APOE epsilon4 allele, may impair clearance of Abeta, and particularly Abeta40, from the brain across the blood-brain barrier, leading to its 'diversion' into perivascular drainage channels, thereby increasing the severity of CAA in such persons.
Shi
Jing
J
Clinical Neuroscience Research Group, University of Manchester, Hope Hospital, Salford, M6 8HD, UK.
Tian
Jinzhou
J
Pritchard
Antonia
A
Lendon
Corinne
C
Lambert
Jean-Charles
JC
Iwatsubo
Takeshi
T
Mann
David M A
DM
D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics; D001812:Blood-Brain Barrier / Q000502:physiology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D006720:Homozygote; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics*; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D011957:Receptors, Opioid / Q000235:genetics*; D012307:Risk Factors; D000094942:Nociceptin Receptor
D020413:3' Untranslated Regions; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human