Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer's disease neurofibrillary and beta-amyloid pathologies

Investigation of the integrity of the ryanodine receptor in Alzheimer's dis ease is important because it plays a critical role in the regulation of cal cium release from the endoplasmic reticulum in brain, impairment of which i s believed to contribute to the pathogenesis of Alzheimer's disease. The pr esent study compared ryanodine receptor levels and their functional modulat ion in particulate fractions from control and Alzheimer's disease temporal cortex, occipital cortex and putamen, Relationships between ryanodine recep tor changes and the progression of Alzheimer's disease pathology were deter mined by examining autoradiographic [H-3]ryanodine binding in entorhinal co rtex/anterior hippocampus sections from 22 cases that had been staged for n eurofibrillary changes and beta-amyloid deposition. A significant (P < 0.02 ) 40% decrease in the B-max fur [H-3]ryanodine binding and significantly hi gher IC50 values for both magnesium and Ruthenium Red inhibition of [H-3]ry anodine binding were detected in Alzheimer's disease temporal cortex partic ulate fractions compared to controls. Immunoblot analyses showed Type 2 rya nodine receptor holoprotein levels to be decreased by 20% (P < 0.05) in the se Alzheimer's disease cases compared to controls. No significant differenc es were detected in [H-3]ryanodine binding comparing control and Alzheimer' s disease occipital cortex or putamen samples. The autoradiography study de tected increased [H-3]ryanodine binding in the subiculum, CA2 and CA1 regio ns in cases with early (stage I-II) neurofibrillary pathology when compared to Stage 0 cases. Analysis of variance of data with respect to the differe nt stages of neurofibrillary pathology revealed significant stage-related d eclines of [H-3]ryanodine binding in the subiculum (P < 0.02) with trends t owards significant decreases in CA1, CA2 and CA4. Post-hoc testing with Fis her's PLSD showed significant reductions (74-94%) of [H-3]ryanodine binding in the subiculum, and CA1-CA4 regions of the late isocortical stage (V-VI) cases compared to the early entorhinal stage I-II cases. [H-3]Ryanodine bi nding also showed significant declines with staging for beta-amyloid deposi tion in the entorhinal cortex (P < 0.01) and CA4 (P < 0.05) with trends tow ards a significant decrease in the dentate gyrus. We conclude that alterations in ryanodine receptor binding and function are very early events in the pathogenesis of Alzheimer's disease, and may be f undamental to the progression of both neurofibrillary and beta-amyloid path ologies. (C) 1999 IBRO. Published by Elsevier Science Ltd.