Fibrillar amyloid beta-protein inhibits the activity of high molecular weight brain protease and trypsin.
The effect of soluble amyloid beta-protein (sAbeta) and fibrillar amyloid beta-protein (fAbeta) on the casein-digesting activity of high molecular weight bovine brain protease (HMW protease) and trypsin was studied. While sAbeta stimulated the casein-digesting activity of HMW protease in a concentration-dependent manner, it did not affect trypsin activity. Structure-activity relationship was studied by testing different soluble and fibrillar Abeta peptides. Various Abeta peptides affected casein-digesting activity of HMW protease differently: sAbeta 1-40 > sAbeta 22-35 = sAbeta 1-11 = sAbeta1-16 > sAbeta 1-28 = sAbeta 31-35, while sAbeta 12-28 and sAbeta 25-35 had no effect. On the other hand, among the fibrillar beta peptides, only fAbeta 1-40 significantly inhibited the casein-digesting activity of HMW protease. Tricine gel electrophoresis showed that sAbeta was digested by trypsin while it remained un-cleaved in the presence of HMW protease. However, fAbeta, a major component of amyloid plaques in Alzheimer's disease, inhibited the casein-digesting activity of both HMW protease and trypsin. fAbetawas found to be resistant to proteolysis by HMW protease and trypsin. The trypsin resistance starts in the early stage of fibrillization of Abeta, i.e., aggregated Abeta. Taken together, these results suggest that fibrillization of Abeta may affect the clearance of Abeta by inhibiting the brain proteases, thereby increasing the concentration of circulating Abeta, that may further increase the Abeta fibrillization.
Chauhan
Ved
V
NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA. ved.chauhan@omr.state.ny.us
Sheikh
Ashfaq M
AM
Chauhan
Abha
A
Spivack
Warren D
WD
Fenko
Michael D
MD
Malik
Mazhar N
MN
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002364:Caseins / Q000378:metabolism; D002449:Cell Aggregation; D002452:Cell Count; D004790:Enzyme Induction / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects*; D016900:Neurofilament Proteins / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D014357:Trypsin / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002364:Caseins; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D010447:Peptide Hydrolases; D014357:Trypsin