Effect of heparin on APP metabolism and Abeta production in cortical neurons.
BACKGROUND
The beta-site APP cleaving enzyme 1 (BACE1) is a major target for drug design in Alzheimer's disease. BACE1 binds strongly to heparin and other glycosaminoglycans, and there is evidence that the enzyme may interact with proteoglycans in vivo. Several studies suggest that heparin or heparan sulfate analogues may have value as therapeutic agents for the treatment of AD.


OBJECTIVE
To determine whether heparin can inhibit Abeta production in cortical neurons by inhibiting BACE1.


METHODS
Cortical neurons from APP (SW) Tg2576 mice were incubated with heparin and the amount of APP processing and Abeta production were measured by enzyme-linked immunosorbent assay and Western blotting.


RESULTS
Treatment of cortical neurons with heparin inhibited Abeta secretion. However, this effect was not mediated via inhibition of BACE1.


CONCLUSIONS
Heparin or other glycosaminoglycans may have value for the treatment of Alzheimer's disease. However, the data do not support the view that a heparin-induced decrease in Abeta secretion is due to inhibition of BACE1.
Menzies Research Institute, University of Tasmania, Hobart, Tas., Australia.
David
D
Klaver
Amos C
AC
Hung
Robert
R
Gasperini
Lisa
L
Foa
Marie-Isabel
MI
Aguilar
David H
DH
Small
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005343:Fibrinolytic Agents; D006493:Heparin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse