Abstract
Inositol 1,4,5-trisphosphate (IP 3), inositol 1,3,4,5-tetrakisphosphate (IP 4) and protein kinase C (PKC) play important roles in the phosphoinositide hydrolysis signal transducing pathway. Several studies have shown severe deficits in both IP 3 receptor levels and PKC levels and activity in Alzheimer's disease brain, although the relationship of these changes to disease pathology is poorly understood. In the present study, we determined the autoradiographic localization of [ 3 H] IP 3 and [ 3 H] IP 4 binding to their calcium mobilizing receptor sites and [ 3 H] phorbol 12,13-dibutyrate ( [ 3 H] PDBu) binding to PKC in sections of entorhinal cortex/hippocampal formation and cerebellum from 24 cases that had 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 [ 3 H] IP 3 binding showed a trend towards a decline with staging for neurofibrillary changes in the entorhinal region (0.05< P<0.10, ANOVA) and subiculum (0.05< P<0.10). In the former region, [ 3 H] IP 3 binding showed a significant decline with staging for amyloid deposition ( P<0.05). [ 3 H] IP 3 binding in the CA1 region showed statistically significant declines with respect to both neurofibrillary changes and amyloid staging ( P<0.05). [ 3 H] IP 3 binding levels in the other hippocampal subregions were too low to quantify accurately. The binding of [ 3 H] IP 4 showed no significant changes with either neurofibrillary changes or amyloid staging in any of the regions investigated. In contrast, [ 3 H] PDBu binding showed significant declines with neurofibrillary staging in the entorhinal 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 dentate gyrus ( P<0.0001). Of these regions, only the subiculum showed a significant decline of [ 3 H] PDBu binding with amyloid staging. There were no significant neurofibrillary or amyloid stage-related changes in either [ 3 H] IP 3, [ 3 H] IP 4 or [ 3 H] PDBu binding in the molecular layer of the cerebellum. These findings suggest that reduced IP 3 receptor and PKC levels in the entorhinal cortex/hippocampal formation reflect and may be important for the progression of Alzheimer's disease neurofibrillary pathology. The data also suggests that hippocampal IP 3 receptor loss is related to the extent of amyloid deposition.
Published Version
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