Biochemical differentiation of cholinesterases from normal and Alzheimer's disease cortex.
In Alzheimer's disease, histochemically visualized cholinesterases with altered pH optimum for activity and inhibitable by indoleamines and the protease inhibitor bacitracin emerge in association with plaques and tangles. It has been suggested that these cholinesterases may participate in the pathologic process. However, it is not known whether the properties of cholinesterases observed in Alzheimer's disease are due to requirements of histochemical procedures or actual biochemical properties of these enzymes. Using biochemical assays of acetylcholinesterase and butyrylcholinesterase activities, we demonstrate here that serotonin and bacitracin result in a significantly greater and dose-dependent inhibition of cholinesterases in Alzheimer's disease cortex when compared with age-matched controls. In contrast, variations in pH did not distinguish cholinesterases in Alzheimer's disease and control cortex. We also confirmed significant reduction of acetylcholinesterase activity in Alzheimer's disease cortex and increased butyrylcholinesterase activity that only approached significance. We conclude that inhibition by indoleamines and bacitracin is a biochemical characteristic of a proportion of cholinesterases in Alzheimer's disease that most likely represents the pool associated with plaques and tangles. Most of the available cholinesterase inhibitors are relatively incapable of inhibiting cholinesterases associated with plaques and tangles. The findings of the present investigation open the way for attempts to isolate cholinesterases associated with plaques and tangles and design or discovery of inhibitors specifically targeted to cholinesterases in these lesions.
Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Alexis
A
Ciro
Joon
J
Park
Gary
G
Burkhard
Nicole
N
Yan
Changiz
C
Geula
D000110:Acetylcholinesterase / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001344:Autopsy; D001414:Bacitracin / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D017830:Octoxynol / Q000494:pharmacology; D011136:Polysorbates / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology
D003902:Detergents; D004791:Enzyme Inhibitors; D011136:Polysorbates; D001414:Bacitracin; D012701:Serotonin; D017830:Octoxynol; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Alzheimer Dis Assoc Disord. 1995;9 Suppl 2:23-8
8534419
Acta Neuropathol. 2003 Feb;105(2):145-56
12536225
Biochem Pharmacol. 1982 Jul 15;31(14):2319-25
7126246
Ann Neurol. 1994 Nov;36(5):722-7
7979218
Neurobiol Dis. 2002 Feb;9(1):88-93
11848688
Cereb Cortex. 1996 Mar-Apr;6(2):165-77
8670647
Acta Neuropathol. 1993;85(4):362-9
8480510
J Neuropathol Exp Neurol. 2008 Apr;67(4):309-18
18379437
Neurobiol Aging. 1981 Winter;2(4):251-6
6174877
Eur J Biochem. 1980 Oct;111(2):511-24
7460914
J Neurochem. 1986 Jul;47(1):263-77
3711902
J Comp Neurol. 1991 Apr 8;306(2):193-220
2050843
Nat Rev Neurosci. 2003 Feb;4(2):131-8
12563284
J Comp Neurol. 1993 Apr 1;330(1):15-31
8468401
Ann Neurol. 1993 Sep;34(3):373-84
8363355
Neuroscience. 1992 Nov;51(1):177-84
1465181
Neuropathol Appl Neurobiol. 1978 Jul-Aug;4(4):273-7
703927
Brain Res. 1991 Feb 1;540(1-2):204-8
2054612
Exp Neurol. 1989 Sep;105(3):221-32
2548888
Brain Res. 1989 Sep 25;498(1):185-9
2790472
Am J Pathol. 2004 Jun;164(6):2163-74
15161650
Biochem Pharmacol. 1961 Jul;7:88-95
13726518
Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):683-6
8421706
Ann Neurol. 1987 Dec;22(6):683-91
3435078
Neuron. 1996 Apr;16(4):881-91
8608006
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7605-10
11404470
J Neurochem. 2000 Sep;75(3):1320-31
10936216
J Neurosci Res. 1994 Apr 15;37(6):777-87
8046778
Neuroscience. 2002;110(4):627-39
11934471
Acta Neuropathol. 1994;87(3):284-92
8009960
Acta Neuropathol. 2002 Jan;103(1):48-58
11837747
J Neurochem. 1994 Feb;62(2):756-63
8294938
Glia. 2004 Jan 15;45(2):208-12
14730714
Curr Med Res Opin. 2001;17(3):159-65
11900310
Cereb Cortex. 1991 Jan-Feb;1(1):103-16
1822725