Amyloid-β 1-42 oligomers enhance mGlu 5 R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

Autor: Ng AN; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK., Salter EW; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, 600 University Avenue, Toronto, ON M5G 1X5, Canada.; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada., Georgiou J; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, 600 University Avenue, Toronto, ON M5G 1X5, Canada.; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada., Bortolotto ZA; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK., Collingridge GL; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, 600 University Avenue, Toronto, ON M5G 1X5, Canada.; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada.
Jazyk: angličtina
Zdroj: IScience [iScience] 2023 Nov 07; Vol. 26 (12), pp. 108412. Date of Electronic Publication: 2023 Nov 07 (Print Publication: 2023).
DOI: 10.1016/j.isci.2023.108412
Abstrakt: Synaptic weakening and loss are well-correlated with the pathology of Alzheimer's disease (AD). Oligomeric amyloid beta (oAβ) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oAβ. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluRs) that is disrupted in rodent models of AD. Exogenous application of oAβ (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu 5 R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both N-methyl-D-aspartate receptors (NMDARs) and complement C5aR1 signaling. Our findings reveal a mechanistic interaction between mGlu 5 R, NMDARs, and the complement system in aberrant synaptic weakening induced by oAβ, which could represent an early trigger of synaptic loss and degeneration in AD.
Competing Interests: The authors declare no competing interests.
(© 2023 The Authors.)
Databáze: MEDLINE
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