LOSS OF INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR-SITES AND DECREASED PKCLEVELS CORRELATE WITH STAGING OF ALZHEIMERS-DISEASE NEUROFIBRILLARY PATHOLOGY

Inositol 1,4,5-trisphosphate (IP3), inositol 1,3,4,5-tetrakisphosphate (IP4) and protein kinase C (PKC) play important roles in the phosphoi nositide hydrolysis signal transducing pathway. Several studies have s hown severe deficits in both IP3 receptor levels and PKC levels and ac tivity in Alzheimer's disease brain, although the relationship of thes e changes to disease pathology is poorly understood. In the present st udy, we determined the autoradiographic localization of [H-3]IP3 and [ H-3]IP4 binding to their calcium mobilizing receptor sites and [H-3]ph orbol 12,13-dibutyrate ([H-3]PDBu) binding to PKC in sections of entor hinal cortex/hippocampal formation and cerebellum from 24 cases that h ad been staged for Alzheimer's disease-related neurofibrillary changes and amyloid deposition according to Braak and Braak [Acta Neuropathol . Berl., 82 (1991) 239-259]. Results indicated that [H-3]IP3 binding s howed a trend towards a decline with staging for neurofibrillary chang es in the entorhinal region (0.05 < P < 0.10, ANOVA) and subiculum (0. 05 < P < 0.10). In the former region, [H-3]IP3 binding showed a signif icant decline with staging for amyloid deposition (P < 0.05). [H-3]IP3 binding in the CA1 region showed statistically significant declines w ith respect to both neurofibrillary changes and amyloid staging (P < 0 .05). [H-3]IP3 binding levels in the other hippocampal subregions were too low to quantify accurately. The binding of [H-3]IP4, showed no si gnificant changes with either neurofibrillary changes or amyloid stagi ng in any of the regions investigated. In contrast, [H-3]PDBu binding showed significant declines with neurofibrillary staging in the entorh inal region (P < 0.01), subiculum (P < 0.001), CA1 (P < 0.001), CA2 (P < 0.001), CA3 (P < 0.001) and CA4 (P < 0.0001) regions and the dentat e gyrus (P < 0.0001). Of these regions, only the subiculum showed a si gnificant decline of [H-3]PDBu binding with amyloid staging. There wer e no significant neurofibrillary or amyloid stage-related changes in e ither [H-3]IP3, [H-3]IP4 or [H-3]PDBu binding in the molecular layer o f the cerebellum. These findings suggest that reduced IP3 receptor and PKC levels in the entorhinal cortex/hippocampal formation reflect and may be important for the progression of Alzheimer's disease neurofibr illary pathology. The data also suggests that hippocampal IP3 receptor loss is related to the extent of amyloid deposition. (C) 1998 Elsevie r Science B.V. All rights reserved.