Reductions in brain phosphatidylinositol kinase activities in Alzheimer's disease

Background: Converging lines of evidence suggest that alterations in the in tracellular trafficking of the amyloid precursor protein, its derivatives, and other relevant proteins may contribute to the pathophysiology of Alzhei mer's disease (AD). Since phosphatidylinositol (PI) kinase plays a pivotal role in the sorting and transport of newly synthesized proteins to their fi nal destinations, we explored the hypothesis that AD is associated with alt erations in the specific activities of these enzymes in postmortem brain ti ssue. Methods: The specific activities of soluble and particulate pools of PI 3-k inase and PI 4-kinase from the frontal cortex were compared between II case s with histopathologically confirmed AD and II nondemented controls matched for sex, race, age at death, and postmortem interval. Potential associatio ns of these activities with sociodemographic and clinical features were als o explored. Results: AD was associated with 43-59% reductions in the specific activitie s of the soluble forms of both lipid kinases; but no significant change in the specific activities of the particulate species. Associations of these s pecific activities with sex, age at onset or death, duration of illness, po stmortem interval, or densities of morphologic lesions in the frontal corte x were not observed among the II AD cases. Conclusions: In addition to regulating protein sorting and trafficking, PI kinases participate in a wide range of cellular processes including protect ion from apoptosis, differentiation and cell growth, regulation of the cyto skeleton, and glucose metabolism. The results of this study suggest that on e or more of these alterations in AD may result from a common abnormality i n PI kinase regulation. (C) 1999 Society of Biological Psychiatry.