A quantitative autoradiographic study of [H-3]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits

The cAMP-dependent protein kinase (PKA) has been implicated in the Alzheime r's disease pathology of abnormal tau phosphorylation leading to neurofibri llary tangle (NFT) formation, as well as in amyloid precursor protein alpha -secretase processing. In the present study, we determined whether [H-3]cAM P binding to cytosolic and particulate PKA showed any relationship to the e xtent of Alzheimer's disease pathology at post-mortem. Autoradiographic [3H ]cAMP binding to cytosolic and particulate PKA was measured in sections of entorhinal cortex/hippocampal formation from 23 cases that had been staged for Alzheimer's disease-related neurofibrillary changes and amyloid deposit s according to Braak and Braak [H. Braak, E. Braak, Neuropathological stagi ng of Alzheimer's-related changes, Acta Neuropathol. 82 (1991) 239-259]. [H -3]cAMP binding to cytosolic PKA showed statistically significant reduction s in the entorhinal cortex (P < 0.01, ANOVA) with respect to neurofibrillar y changes. Post-hoc analysis with Fisher's PLSD test showed significant red uctions of [H-3]cAMP binding to cytosolic PKA at the isocortical stages (V and VI), compared to the non-pathological (O) (by 55%, P < 0.01), transento rhinal (I and II) (by 58%, P < 0.001) and limbic (III and nr) (by 45%, P < 0.05) stages. A significant reduction (by 25%, P < 0.05) was also seen in t he transentorhinal compared to the limbic stages. [H-3]cAMP binding to cyto solic PKA showed no significant alterations with respect to neurofibrillary changes in either the subiculum, CA1-CA4 subfields of the hippocampus or t he dentate gyrus. [H-3]cAMP binding to cytosolic PKA also showed significan t declines in the entorhinal cortex(P < 0.01) and subiculum (P < 0.05) with respect to staging for amyloid deposits. Post-hoc analysis with Fisher's P LSD test showed significant reductions of [H-3]cAMP binding to cytosolic PK A in the entorhinal cortex at amyloid stage C compared to stages O (by 41%, P < 0.01) and A (by 38%, P < 0.01). In the subiculum, there were significa nt reductions of [H-3]cAMP binding at stages C (by 41%, P < 0.01) and B (by 40%, P < 0.05), respectively, compared to stage O. [H-3]cAMP binding to pa rticulate PKA did not show significant relationships to staging for either neurofibrillary changes or amyloid deposits in either the entorhinal cortex or any of the hippocampal subregions. These findings suggest that whereas [H-3]cAMP binding to cytosolic PKA. in the entorhinal cortex is reduced wit h progression of neurofibrillary and amyloid pathology, other hippocampal r egions show a preservation of cytosolic and particulate PKA even in late st age pathologies. (C) 1999 Elsevier Science B.V. All rights reserved.