DIMINISHED [H-3] INOSITOL(1,4,5)P-3, BUT NOT [H-3] INOSITOL(1,3,4,5)P-4 BINDING IN ALZHEIMERS-DISEASE BRAIN

Levels of the calcium mobilising receptors for the phosphoinositide hy drolysis derived second messengers, inositol(1,4,5)trisphosphate [Ins( 1,4,5)P-3] and inositol(1,3,4,5) tetrakis-phosphate [Ins(1,3,4,5)P-4] were compared in the cerebellum, superior temporal and superior fronta l cortex of a series of Alzheimer's disease and matched control cases. Membrane [H-3]Ins(1,4,5)P-3 radioligand binding experiments performed under steady state conditions revealed that the number of Ins(1,4,5)P -3 recognition sites was significantly decreased in all three brain re gions of the Alzheimer's disease cases, compared to controls. In contr ast, [H-3]Ins(1,3,4,5)P-4 binding levels, as assessed in competition a nalyses, were not significantly different between the groups in any br ain region. Moreover, the Hill coefficients for inhibition of [H-3]Ins (1,3,4,5)P-4 binding by non-radioactive Ins(1,3,4,5)P-4 were less than unity in both the control and Alzheimer's disease brains, suggesting that the heterogeneity of these binding sites are also maintained in t he disease. It is concluded that disruptions of the phosphoinositide h ydrolysis pathway in Alzheimer's disease brain are associated with a s elective loss of calcium mobilising Ins(1,4,5)P-3, but not Ins(1,3,4,5 )P-4 receptor sites. These alterations may contribute to an altered ca lcium homeostasis in Alzheimer's disease, as well as providing one rea son for the lack of success of cholinergic replacement therapies aimed at enhancing muscarinic receptor-mediated phosphatidylinositol hydrol ysis.