INHIBITION OF CYTOSOLIC HUMAN FOREBRAIN CHOLINE-ACETYLTRANSFERASE ACTIVITY BY PHOSPHO-L-SERINE - A PHOSPHOMONOESTER THAT ACCUMULATES DURINGEARLY STAGES OF ALZHEIMERS-DISEASE

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.