Beta-amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants.
The beta-amyloid (A beta) peptide is present both in serum and in platelets, however it is unclear whether A beta plays a role in platelet function. We have now investigated the effects of soluble A beta on platelet function and have found that low levels (0.1-1 nM) of soluble A beta augment ADP-dependent platelet aggregation and translocation of focal adhesion kinase to the platelet cytoskeleton. Addition of A beta to gel-filtered platelets along with concentrations of adenosine diphosphate (ADP) producing submaximal aggregation responses increased the aggregation response by over 2-fold depending on the ADP:A beta ratios. The structure activity requirements for A beta activity showed intriguing constraints. Only full length A beta has significant activity. Truncated A beta peptides, such as A beta(1-16) or A beta(25-35), or reverse A beta(40-1) all show little or no activity. We also examined the activity of mutant A beta peptides, corresponding with the APP(692A-G) and APP(693E-Q) (at A beta21 and A beta22, respectively) which are found in familial Alzheimer's disease and hereditary cerebral hemorrhagic amyloidosis, Dutch type (HCHWA-D), and found that these peptides showed little or no activity. These results suggest that A beta interacts with platelets in a highly specific manner and may play a role in regulating platelet function.
Wolozin
B
B
Section on Geriatric Psychiatry, NIMH, Bethesda, MD 20892, USA. bwolozi@wpo.it.luc.edu
Maheshwari
S
S
Jones
C
C
Dukoff
R
R
Wallace
W
W
Racchi
M
M
Nagula
S
S
Shulman
N R
NR
Sunderland
T
T
Bush
A
A
D000244:Adenosine Diphosphate / Q000494:pharmacology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D000001:Calcimycin / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000097:blood; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000097:blood
D016229:Amyloid beta-Peptides; D015815:Cell Adhesion Molecules; D010446:Peptide Fragments; D000001:Calcimycin; D000244:Adenosine Diphosphate; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human