EVIDENCE FOR A SELECTIVE DECREASE IN TYPE-1 PHOSPHATIDYLINOSITOL KINASE-ACTIVITY IN BRAINS OF PATIENTS WITH ALZHEIMERS-DISEASE

We have previously shown that phosphatidylinositol (PI) kinase activity is 40-50% lower in cytosolic fractions of neocortical regions from brains of patients with Alzheimer's disease (AD) in contrast to phosphatidylinositol phosphate (PIP) kinase activity, which was not affected. After preparing different enzyme fractions by solubilization, the PI kinase activity in the salt-solubilized protein preparation of the temporal cortex of AD brains was predominantly affected (70% decrease). PIP kinase activity in AD brains was not different from that of control brains in any of the fractions tested. PI kinase in the salt-solubilized fractions was inhibited (-75%) by 1% Triton X-100, whereas the PI kinase in the detergent solubilized protein preparation was stimulated (+80%) by 1% Triton X-100. PI kinase activity in the salt-solubilized protein preparation was almost unaffected by adenosine in contrast to PI kinase activity in the detergent solubilized protein preparation, which was strongly inhibited by adenosine. These results indicate that the PI kinase that is specifically affected in AD is the PI 3-kinase, or type 1 PI kinase, because the fraction which was affected most severely has (1) a cytosolic localization; (2) a high sensitivity to inhibition by the non-ionic detergent Triton X-100, and (3) an insensitivity to adenosine inhibition, which are characteristic features of type 1 PI kinase. The relevance of our findings is that type 1 PI kinase is thought to be involved in the regulation of cytoskeletal turnover processes. In this context, changes in the type 1 PI kinase activity could be related to the cellular pathology of AD because neurofibrillary tangles, which are a prominent feature of AD, are partially composed of wrongly phosphorylated cytoskeletal components.