The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Autor: Soares C; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Da Ros LU; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Machado LS; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Rocha A; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Lazzarotto G; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Carello-Collar G; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., De Bastiani MA; Graduate Program in Biological Sciences: Pharmacology and Therapeutics, UFRGS, Porto Alegre, Brazil., Ferrari-Souza JP; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Lussier FZ; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Souza DO; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.; Department of Biochemistry, UFRGS, Porto Alegre, Brazil., Rosa-Neto P; Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada.; Douglas Research Institute, Le Centre Intégré Universitaire de Santé et de Services Sociaux de l'Ouest-de-l'Île-de-Montréal, McGill University, Montreal, QC, Canada.; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.; Department of Psychiatry, McGill University, Montreal, QC, Canada., Pascoal TA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA., Bellaver B; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Zimmer ER; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br.; Graduate Program in Biological Sciences: Pharmacology and Therapeutics, UFRGS, Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br.; Department of Biochemistry, UFRGS, Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br.; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. eduardo.zimmer@ufrgs.br.; Brain Institute of Rio Grande do Sul - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br.; Department of Pharmacology, UFRGS, Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Jul; Vol. 29 (7), pp. 2261-2273. Date of Electronic Publication: 2024 Feb 16.
DOI: 10.1038/s41380-024-02473-0
Abstrakt: Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I 2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I 2  = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I 2  = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I 2  = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I 2  = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I 2  = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I 2  = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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