Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer's disease and dementia with Lewy bodies correlates with stage of Alzheimer's-disease-related changes.
The aim of the present work was to analyze the status of metabotropic glutamate receptors (mGluRs) in the frontal cortex (area 8) from ten cases with common form DLB (cDLB) and eleven cases with pure AD in comparison with five age-matched controls. mGluRs, determined by radioligand binding assays, were significantly decreased in cerebral cortex in cDLB. This decrease was already present in cases with early AD changes not involving the frontal cortex, but dramatically correlated with AD neuropathological changes, at its greatest in isocortical stages, which was associated with a decrease in the expression levels of mGluR1 detected by Western blotting. Moreover, mGluRs analyzed in pure AD were lower than those obtained in cDLB and also correlated with progression of illness. On the other hand, the expression levels of phospholipase Cbeta1 (PLCbeta1) isoform, which is the effector of group I mGluRs, was decreased in parallel in cDLB cases. Finally, the PLCbeta1 decrease was associated with reduced GTP- and l-glutamate-stimulated PLC activity in both cDLB and AD cases. These results show that group I mGluRs/PLC signaling are down-regulated and desensitized in the frontal cortex in cDLB and AD cases and that these modifications worsen with progression of AD changes in the cerebral neocortex. Therefore, group I mGluR dysfunction may be implicated in the pathogenesis of cognitive impairment and dementia in common form of DLB and pure AD.
Albasanz
José Luis
JL
Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias Químicas, Area de Bioquímica, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain.
Dalfó
Esther
E
Ferrer
Isidro
I
Martín
Mairena
M
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001667:Binding, Competitive / Q000502:physiology; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D020961:Lewy Body Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D054799:Phospholipase C beta; D011869:Radioligand Assay; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism*
D007527:Isoenzymes; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D006160:Guanosine Triphosphate; D010738:Type C Phospholipases; D054799:Phospholipase C beta