DECREASED INOSITOL (1,4,5)-TRISPHOSPHATE RECEPTOR LEVELS IN ALZHEIMERS-DISEASE CEREBRAL-CORTEX - SELECTIVITY OF CHANGES AND POSSIBLE CORRELATION TO PATHOLOGICAL SEVERITY

We used immunoblotting and radioligand binding techniques to compare l evels of the calcium-mobilizing receptor for the phosphoinositide hydr olysis-derived intracellular second messenger inositol (1,4,5)-trispho sphate (IP3) in post mortem samples from the temporal, frontal and par ietal cortices of eight Alzheimer's disease (AD) and eight matched con trol cases. Immunoblotting with an antibody directed against the C-ter minal end of the rat type I IP3-receptor showed that IP3-receptor prot ein levels were significantly reduced in the temporal (to 59 +/- 6% of controls, P = 0.0002) and frontal (to 62 +/- 10% of controls, P = 0.0 4), but not in the parietal cortices (to 63 +/- 13% of controls, P = 0 .1) of the AD cases, compared to controls. The number of [H-3]IP3 radi oligand binding sites was significantly decreased in the temporal cort ex, but not frontal and parietal cortices, of the AD brains. The decre ased levels of both immunoreactive IP3-receptor protein and [H-3]IP3 b inding in the temporal cortex correlated with a semi-quantitative scor e for the severity of AD neuropathology No significant changes were se en in the levels of glial fibrillary acidic protein, synaptophysin or phosphate-activated glutaminase, as markers for astrocytes, neuronal v esicles and mitochondria, respectively. It is concluded that in affect ed AD brain regions, the IP3-receptor may represent a sensitive target for proteolysis, possibly mediated by activation of the Ca2+-activate d neutral protease calpain. These degenerative changes may in part be responsible for the disruption of Ca2+ homeostasis in AD-sensitive neu rons. (C) 1996 Academic Press Limited.