Decreased inositol (1,4,5)-trisphosphate receptor levels in Alzheimer's disease cerebral cortex: selectivity of changes and possible correlation to pathological severity.
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.
Haug
L S
LS
Neurochemical Laboratory, University of Oslo, Norway.
Ostvold
A C
AC
Cowburn
R F
RF
Garlind
A
A
Winblad
B
B
Bogdanovich
N
N
Walaas
S I
SI
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001344:Autopsy; D015415:Biomarkers; D015220:Calcium Channels / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005972:Glutaminase / Q000032:analysis; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012016:Reference Values; D012044:Regression Analysis; D015290:Second Messenger Systems; D018709:Statistics, Nonparametric; D016708:Synaptophysin / Q000032:analysis; D013702:Temporal Lobe / Q000378:metabolism*
D015415:Biomarkers; D015220:Calcium Channels; D005904:Glial Fibrillary Acidic Protein; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D016708:Synaptophysin; D015544:Inositol 1,4,5-Trisphosphate; D005972:Glutaminase