Possible reverse transport of beta-amyloid peptide across the blood-brain barrier.
Our experiments were performed to test the hypothesis that human beta-amyloid peptide 42 (beta A) is able to enter and exit the brain parenchyma through the blood-brain barrier. In an effort to determine the effect of beta A in an animal model, we have injected beta A i.v. into rats following single and repeated brain ischemia. Rats were sacrificed at 3 and 12 months after injection and beta A was localized by monoclonal antibody (mAb) 4G8. The present observations revealed an abundant presence of beta A in the extracellular space of the brain, which appeared to be dilated, and a vigorous uptake of beta A into the cytoplasm of endothelial and ependymal cells, pericytes, astrocytes and neurons. Some of the beta A deposits were associated and/or had migrated to the vessels and to the ventricles, and by 3 months a significant amount of beta A was directly associated with the vessels and was observed inside the ventricular space. Virtually no soluble and aggregating beta A was found in brain tissue 1 year later. This suggests that phagocytic pericytes and astrocytes take up exogenous beta A in an attempt to clear the peptide from the brain extracellular space and deliver it to the circulation. Further, direct removal of beta A from the ventricles by the bloodstream is also possible. These observations suggest that a reverse transport of beta A across endothelial cells of microvessels represents one of the possible mechanisms responsible for removal of extravasated beta A. The findings of the present study indicate that in normal conditions beta A is rapidly cleared from the cerebrospinal fluid and brain parenchyma, suggesting that irreversible changes in the physico-chemical properties of the cerebrovascular endothelial cell surface are involved in beta A deposition in the brain in Alzheimer's disease (AD).
Pluta
R
R
Department of Neuropathology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Misicka
A
A
Barcikowska
M
M
Spisacka
S
S
Lipkowski
A W
AW
Januszewski
S
S
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000473:pathology; D002552:Cerebral Ventricles / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D002546:Ischemic Attack, Transient / Q000473:pathology*; D010446:Peptide Fragments / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)