Brain endothelial cell enzymes cleave platelet-retained amyloid precursor protein.
We have previously demonstrated that thrombin-activated platelets from patients with advanced Alzheimer's disease (AD) retain significantly more surface membrane-bound amyloid precursor protein (mAPP) than platelets from non-demented age-matched individuals (AM). We have studied interactions between these platelets and the cerebrovascular endothelium to which activated platelets adhere in a model system, investigating their involvement in the formation of amyloid beta peptide (Abeta) deposits in AD patients. We report here that there appear to be alpha and beta secretase-like activities in primary human blood brain barrier endothelial cell (BEC) cultures from both AD patients and AM control subjects (AD-BEC and AM-BEC, respectively) as well as a gamma secretase-like activity that appears only in AD-BEC. No such activities were observed in human umbilical vein endothelial cells (HUVECs). Furthermore, there is more penetration of the platelet-released products platelet factor 4 and soluble APP through the BEC layer grown from AD patients than that grown from AM individuals, whereas none penetrate through a HUVEC layer. Thus the interaction between platelets, the APP they have retained or released, and cerebral vascular endothelial cells may be at least partially responsible for amyloidogenic deposits around the cerebral vasculature of AD patients.
Davies
T A
TA
Boston University School of Medicine, Massachusetts 02118, USA.
Billingslea
A M
AM
Long
H J
HJ
Tibbles
H
H
Wells
J M
JM
Eisenhauer
P B
PB
Smith
S J
SJ
Cribbs
D H
DH
Fine
R E
RE
Simons
E R
ER
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D001792:Blood Platelets / Q000378:metabolism; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D010450:Endopeptidases / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014471:Umbilical Veins / Q000166:cytology
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human