Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF.
Cerebral deposition of amyloid beta protein (A beta) is an early and critical feature of Alzheimer's disease. A beta production requires the proteolytic release of A beta from the beta-amyloid precursor protein (beta APP). Thus, inhibition of A beta release is a prime therapeutic goal. Here, we show that the broad spectrum, irreversible serine protease inhibitor, AEBSF, inhibits the constitutive production of A beta in five different human cell lines, both neural and nonneural. AEBSF also stabilizes full-length beta APP and enhances alpha-secretion, as shown by an increase in the proteolytic derivative, alpha-APPS. Further, we demonstrate that the inhibitory effect of AEBSF is specific for A beta proteins starting at Aspartate 1, suggesting that AEBSF directly inhibits beta-secretase, the Methionine-Aspartate (Met-Asp)-cleaving enzyme. These results indicate that specific inhibition of this A beta-generating protease is possible in living human neural cells and provide information about the characteristics of this as yet unidentified enzyme.
Citron
M
M
Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Diehl
T S
TS
Capell
A
A
Haass
C
C
Teplow
D B
DB
Selkoe
D J
DJ
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; C002010:4-(2-aminoethyl)benzenesulfonylfluoride