Elsevier

Neurobiology of Disease

Volume 20, Issue 3, December 2005, Pages 685-693
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2005.05.001Get rights and content

Abstract

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 phospholipase1 (PLCβ1) isoform, which is the effector of group I mGluRs, was decreased in parallel in cDLB cases. Finally, the PLCβ1 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.

Introduction

Glutamate is the main excitatory neurotransmitter in the central nervous system which has been implicated in several physiological and pathological processes (Bordi and Ugolini, 1999, Conn and Pin, 1997). The different actions of glutamate are mediated through glutamate receptor binding, which has been classified into ionotropic and metabotropic. Metabotropic glutamate receptors (mGluRs) are coupled, through G-proteins, to different effector systems, including phospholipase C (PLC) and adenylyl cyclase (AC). They have been classified in three groups on the basis of their pharmacological profile, molecular properties, and transduction mechanisms. Group I receptors (mGlu1, mGlu5) are coupled to PLC activation, through Gq/11 proteins, whereas groups II and III are coupled to AC inhibition, through Gi/o proteins (Conn and Pin, 1997, Pin and Duvoisin, 1995).

Dementia with Lewy bodies (DLB) is a primary neurodegenerative disease in old age sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD) (Baba et al., 1998, Campbell et al., 2000, Hashimoto and Masliah, 1999, Ince et al., 1998, McKeith, 2002, McKeith et al., 1996). Clinical features of DLB include parkinsonism, fluctuating disturbances of consciousness, recurrent visual hallucinations, sleep disorders, and cognitive decline which progresses to dementia (Piggott et al., 1999). Lewy bodies, which are the hallmark of PD and DLB, are neural inclusions composed of abnormally phosphorylated neurofilament proteins aggregated with ubiquitin and α-synuclein. Changes characteristic of AD, including senile plaques and neurofibrillary tangles, are also present in many patients with DLB (Hansen and Samuel, 1997, Ince and McKeith, 2003, Kosaka, 1993, Kosaka and Iseki, 1996). Cases with no or with minor AD-related associated changes are considered pure forms of DLB, whereas cases with marked AD-related pathology are considered common forms of DLB (Kosaka and Iseki, 1996). Categorization of Lewy changes in DLB can be carried out for operational purposes following the proposal of Braak et al. for the staging of brain pathology related to sporadic Parkinson's disease (Braak et al., 2003). According to this nomenclature, stage 5 involves sensory association areas of the neocortex and prefrontal cortex, whereas stage 6 affects first order sensory association areas and pre-motor areas. On the other hand, AD pathology has been categorized as stages: I–II: entorhinal, III–IV: limbic, and V–VI: isocortical of neurofibrillar (NF) degeneration; and as stages: 0: no deposition, A: basal neocortex, B: cortical association areas, and C: entire cerebral neocortex of amyloid-β (Aβ) deposition (Braak and Braak, 1999).

Alterations in neurotransmitter receptors have been detected in AD and PD that likely contribute to their clinical features and neuropathology. The central cholinergic pathway is severely affected in AD, PD, and DLB (Court et al., 2001, Martin-Ruiz et al., 2002, Pimlott et al., 2004, Suzuki et al., 2002). It is worth stressing that muscarinic M1 receptor binding is extensively reduced in the temporal and parietal neocortex (Ballard et al., 2002), and down-regulation of nicotinic receptor has been detected in dopaminergic neurons in DLB (Perry et al., 1995). Moreover, cholinergic neurotransmission in the cerebral cortex is severely impaired in DLB, even more than what is observed in AD (Perry et al., 1994). Serotonin receptor binding is reduced in the temporal cortex of patients with AD, PD, and DLB (Cheng et al., 1991). Disruption of the nigrostriatal and mesocorticolimbic dopaminergic systems is characteristic of PD and DLB (Sweet et al., 1998).

In a previous report, we have shown abnormal α-synuclein/PLCβ1 interactions associated with impaired mGluR function in the cerebral cortex of DLB (Dalfó et al., 2004). The aim of the present work was to study group I metabotropic glutamate receptor (mGluR) transduction pathway in the frontal cortex of ten cases of DLB with AD-related associated changes (common form of DLB), eleven pure AD cases, and five age-matched controls, by using glutamate binding assays, Western blotting, and determination of PLC expression levels and activity. Special attention has been paid in comparing modifications of group I mGluRs in DLB cases (n = 4) with no AD-related changes in the neocortex (stages I–II of NF degeneration and 0/A of Aβ) and in cases (n = 6) with marked AD-related isocortical pathology (stages V–VI of NF degeneration and stage C of Aβ deposition). The goal was therefore double, first to know whether group I mGluRs are modified in common form of DLB, and second whether these modifications are further hampered by AD progression.

Section snippets

Materials

l-[3H]Glutamate (48.1 Ci/mmol) and phosphatidyl[2-3H] inositol 4,5-bisphosphate (1 Ci/mmol) were purchased from PerkinElmer (Madrid, Spain). l-glutamic and α-amino-3-hydroxy-5-methyl-isoxazole-4 propionic (AMPA) acids were obtained from Tocris (London, UK). N-methyl-d-aspartic acid (NMDA), kainate, and dl-threo-β-hydroxyaspartic acid were from Sigma (Madrid, Spain). GTP was from Roche (Madrid, Spain). Nitrocellulose membrane and electrophoresis reagents were from Bio-Rad Laboratories.

Metabotropic glutamate receptors in DLB and AD

Metabotropic glutamate receptor binding was measured in brain membranes using l-[3H]Glutamate as radioligand under conditions in which binding to ionotropic glutamate receptors is blocked. l-[3H]Glutamate binding to membranes from human brain was saturable and showed kinetic parameters corresponding to a single binding site. The total number of metabotropic glutamate receptors (Bmax) was significantly decreased (80% of controls, P < 0.01) in membranes from DLB patients, as can be observed in

Discussion

Glutamatergic pathways have been implicated in the pathophysiology of a number of neurological disorders including AD and vascular dementia (Francis, 2003, Louzada et al., 2001, Meldrum and Garthwaite, 1990). At physiological concentrations, glutamate mediates learning and memory processes (Riedel et al., 2003). However, at high concentrations, glutamate acts as a neurotoxin and promotes neuronal cell injury and death in animal models (Rao et al., 2001, Rothstein, 1996) and, probably, in some

Acknowledgments

This work was supported in part by FIS grants P102/0004, G03/167, and C03/06 and by Brain Net II contract, grant GC03017 from the Consejería de Sanidad of JCCM, BFI2002-00277 from McyT, and grants 04/301-01 and 04/301-02 from Fundació “La Caixa”. We wish to thank T. Yohannan for editorial assistance.

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