Decreased inositol (1,4,5)-trisphosphate receptor levels in Alzheimer's disease cerebral cortex: selectivity of changes and possible correlation to pathological severity.

ABSTRACT

We used immunoblotting and radioligand binding techniques to compare levels of the calcium-mobilizing receptor for the phosphoinositide hydrolysis-derived intracellular second messenger inositol (1,4,5)-trisphosphate (IP3) in post mortem samples from the temporal, frontal and parietal cortices of eight Alzheimer's disease (AD) and eight matched control cases. Immunoblotting with an antibody directed against the C-terminal end of the rat type I IP3-receptor showed that IP3-receptor protein levels were significantly reduced in the temporal (to 59 +/- 6% of controls, P = 0.0002) and frontal (to 62 +/- 10% of controls, P = 0.04), but not in the parietal cortices (to 63 +/- 13% of controls, P = 0.1) of the AD cases, compared to controls. The number of [3H]IP3 radioligand binding sites was significantly decreased in the temporal cortex, but not frontal and parietal cortices, of the AD brains. The decreased levels of both immunoreactive IP3-receptor protein and [3H]IP3 binding in the temporal cortex correlated with a semi-quantitative score for the severity of AD neuropathology. No significant changes were seen in the levels of glial fibrillary acidic protein, synaptophysin or phosphate-activated glutaminase, as markers for astrocytes, neuronal vesicles and mitochondria, respectively. It is concluded that in affected AD brain regions, the IP3-receptor may represent a sensitive target for proteolysis, possibly mediated by activation of the Ca(2+)-activated neutral protease calpain. These degenerative changes may in part be responsible for the disruption of Ca2+ homeostasis in AD-sensitive neurons.