Beta amyloid fragments derived from activated platelets deposit in cerebrovascular endothelium: usage of a novel blood brain barrier endothelial cell model system.
Amyloid precursor protein (A betaPP) processing results in generation of amyloid beta peptide (A beta) which deposits in the brain parenchyma and cerebrovasculature of patients with Alzheimer's disease (AD). Evidence that the vascular deposits derive in part from A betaPP fragments originating from activated platelets includes findings that individuals who have had multiple small strokes have a higher prevalence of AD compared to individuals who have taken anti-platelet drugs. Thus, determination of whether platelet A betaPP fragments are capable of traversing the blood-brain barrier (BBB) is critical. We have established that activated platelets from patients with AD retain more surface transmembrane-bound A betaPP (mA betaPP) than control platelets. We report here that this mA betaPP can be cleaved to A beta-containing fragments which pass through a novel BBB model system. This model utilizes human BBB endothelial cells (BEC) isolated from brains of patients with AD. These BEC, after exposure to activated platelets which have been surface-labeled with fluorescein and express surface-retained mA betaPP, cleave fluorescein-tagged surface proteins, including mA betaPP, resulting in passage to the BEC layer The data confirm that BEC contribute to processing of platelet-derived mA betaPP and show that the processing yields A beta containing fragments which could potentially contribute to cerebrovascular A beta deposition.
Davies
T A
TA
Biochemistry Department, Boston University School of Medicine, MA 02118, USA. davies@biochem.bumc.bu.edu
Long
H J
HJ
Eisenhauer
P B
PB
Hastey
R
R
Cribbs
D H
DH
Fine
R E
RE
Simons
E R
ER
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000032:analysis; D005456:Fluorescent Dyes / Q000032:analysis; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D015539:Platelet Activation; D011499:Protein Processing, Post-Translational
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D016650:Fluorescein-5-isothiocyanate