In vitro evidence that beta-amyloid peptide 1-40 diffuses across the blood-brain barrier and affects its permeability.
Beta amyloid peptides are major insoluble constituents of amyloid fibrils in senile plaques and cerebrovascular deposits, both characteristic of Alzheimer disease (AD). Low concentrations of soluble forms of amyloid peptides are also present in normal CSF. We previously demonstrated that the 40 amino acid form of soluble beta-amyloid peptide (sAbeta) is rapidly cleared from rat CSF into blood. Herein we hypothesized that a saturable, outwardly directed flux of this peptide occurs at the blood-brain barrier (BBB) and tested whether supraphysiological (possibly pathological) concentrations of sAbeta could alter the permeability of this barrier to a paracellular tracer, polyethylene glycol (PEG). Using an in vitro model of BBB, we showed that influx and efflux of sAbeta were equal, modest (60%-160% greater than that of PEG), and not saturable. These observations suggest that sAbeta moved across the monolayer by a diffusional process, and not via a transporter. PEG flux was doubled immediately after the luminal concentration of cold sAbeta was raised to 5 microM, and was doubled 150 min after the abluminal concentration of sAbeta was increased to 5 microM. Pathological elevations of sAbeta concentration in plasma or brain interstitial fluid may, therefore, alter the permeability of brain capillaries in vivo.
Strazielle
N
N
INSERM U433 Faculté de Médecine Laennec, Lyon, Frances.
Ghersi-Egea
J F
JF
Ghiso
J
J
Dehouck
M P
MP
Frangione
B
B
Patlak
C
C
Fenstermacher
J
J
Gorevic
P
P
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001812:Blood-Brain Barrier / Q000502:physiology*; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D008970:Molecular Weight; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D012997:Solvents / Q000737:chemistry / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012997:Solvents; C078592:amyloid beta-protein (1-40); D011092:Polyethylene Glycols