EFFECTS OF ALZHEIMERS-DISEASE-RELATED BETA-AMYLOID PROTEIN-FRAGMENTS ON ENZYMES METABOLIZING PHOSPHOINOSITIDES IN BRAIN

Phosphatidylinositol 4-kinase (PI 4-kinase) and phosphatidylinositol 4 -phosphate kinase (PIP kinase) were assayed in membranes prepared from samples of human frontal cortex initially frozen at autopsy. PI 4-kin ase activity was significantly lower in Alzheimer's disease patients r elative to age-matched controls or patients with Parkinson's disease. PIP kinase was not different in Alzheimer's versus age-matched control s. The beta amyloid protein fragment 1-40 inhibited PI 4-kinase activi ty in assays of control human or rat cortical membranes. Fragments 1-2 8 and 25-35 could not mimic the effects of fragment 1-40 while a rever se peptide 40-1 was equipotent. The inhibition of PI 4-kinase by fragm ent 1-40 was competitive with substrate. The beta amyloid protein frag ments had diverse effects on phosphoinositide-specific phospholipase C (PI-PLC) as assayed in rat cortical membranes. Low concentrations of fragment 1-40 stimulated, while high concentrations of 1-40 or 40-1 in hibited PI-PLC activity. Fragment 25-35 stimulated PI-PLC nearly 3-fol d, while fragment 1-28 had only minor effects on the enzyme. The resul ts suggest alterations in phosphoinositide metabolism in Alzheimer's d isease which could affect signal transduction and/or cytoskeletal orga nization.