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 activit y is 40-50% lower in cytosolic fractions of neocortical regions from b rains of patients with Alzheimer's disease (AD) in contrast to phospha tidylinositol 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 tem poral cortex of AD brains was predominantly affected (70% decrease). P IP kinase activity in AD brains was not different from that of control brains in any of the fractions tested. PI kinase in the salt-solubili zed 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 sev erely has (1) a cytosolic localization; (2) a high sensitivity to inhi bition by the non-ionic detergent Triton X-100, and (3) an insensitivi ty 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 pro cesses. In this context, changes in the type 1 PI kinase activity coul d be related to the cellular pathology of AD because neurofibrillary t angles, which are a prominent feature of AD, are partially composed of wrongly phosphorylated cytoskeletal components.