Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans.
Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Abeta is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated that Abeta40 and Abeta42 interact directly with P-gp. We therefore hypothesized that Abeta accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Abeta, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Abeta40- and Abeta42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 ( ) polymorphisms (exon 2, G-1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Abeta40 and Abeta42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Abeta may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Abeta from brain.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000483:Alleles; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001344:Autopsy; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E