Reductions in brain phosphatidylinositol kinase activities in Alzheimer's disease

Converging lines of evidence suggest that alterations in the intracellular trafficking of the amyloid precursor protein, its derivatives, and other relevant proteins may contribute to the pathophysiology of Alzheimer's disease (AD). Since phosphatidylinositol (PI) kinase plays a pivotal role in the sorting and transport of newly synthesized proteins to their final destinations, we explored the hypothesis that AD is associated with alterations in the specific activities of these enzymes in postmortem brain tissue.

The specific activities of soluble and particulate pools of PI 3-kinase and PI 4-kinase from the frontal cortex were compared between 11 cases with histopathologically confirmed AD and 11 nondemented controls matched for sex, race, age at death, and postmortem interval. Potential associations of these activities with sociodemographic and clinical features were also explored.

AD was associated with 43-59% reductions in the specific activities of the soluble forms of both lipid kinases; but no significant change in the specific activities of the particulate species. Associations of these specific activities with sex, age at onset or death, duration of illness, postmortem interval, or densities of morphologic lesions in the frontal cortex were not observed among the 11 AD cases.

In addition to regulating protein sorting and trafficking, PI kinases participate in a wide range of cellular processes including protection from apoptosis, differentiation and cell growth, regulation of the cytoskeleton, and glucose metabolism. The results of this study suggest that one or more of these alterations in AD may result from a common abnormality in PI kinase regulation.