INHIBITION OF CYTOSOLIC HUMAN FOREBRAIN CHOLINE-ACETYLTRANSFERASE ACTIVITY BY PHOSPHO-L-SERINE - A PHOSPHOMONOESTER THAT ACCUMULATES DURINGEARLY STAGES OF ALZHEIMERS-DISEASE
C. Andriamampandry et Jn. Kanfer, INHIBITION OF CYTOSOLIC HUMAN FOREBRAIN CHOLINE-ACETYLTRANSFERASE ACTIVITY BY PHOSPHO-L-SERINE - A PHOSPHOMONOESTER THAT ACCUMULATES DURINGEARLY STAGES OF ALZHEIMERS-DISEASE, Neurobiology of aging, 14(4), 1993, pp. 367-372
There is no satisfactory explanation for the cholinergic deficit chara
cteristic of Alzheimer's disease. We have performed a series of experi
ments which demonstrate that (a) an inhibitor of cytosolic human brain
choline acetyltransferase is present in the cytosol of Alzheimer brai
n tissue, (b) human brain cytosolic choline acetyltransferase activity
is inhibited by phospho-L-serine in a competitive manner. Cytosol was
prepared from human forebrain or amygdala and the K(m) for choline an
d acetyl CoA of the choline acetyltransferase were 750 muM and 12.5 mu
M, respectively. Phospho-L-serine was found to be a competitive inhibi
tor of this enzyme with respect to choline but not with respect to ace
tyl CoA with a Ki of 750 muM for the human forebrain and 3 mM for huma
n amygdala. These concentrations of phospho-L-serine are present in br
ain tissue at early stages of Alzheimer's disease. Several other phosp
homonoesters and phosphodiesters that are increased in Alzheimer's dis
ease were either less inhibitory or without effect. The addition of he
at denatured and non-heat denatured cytosol from Alzheimers forebrain
inhibited the choline acetyltransferase activity present in control hu
man brain cytosol. The inhibitory activity of the Alzheimers cytosol w
as retained in TCA deproteinized samples and removed by dialysis or by
alkaline phosphatase treatment. Dialysis of the cytosol increased the
choline acetyltransferase activity of 5 of 8 Alzheimer's disease samp
les from 21 to 118% with p values of <0.025 or <0.001, respectively. T
hese observations provide evidence that an endogenous non-proteinaceou
s, dialyzable, phosphomonoester, present in Alzheimers brain inhibits
the choline acetyltransferase of both control and Alzheimers brain. Th
erefore, an alteration in membrane phospholipid metabolism could secon
darily contribute to the hypocholinergic state observed in Alzheimer's
disease.