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Amyloid Fibril–Induced Astrocytic Glutamate Transporter Disruption Contributes to Complement C1q-Mediated Microglial Pruning of Glutamatergic Synapses

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Abstract

The complement C1q plays a critical role in microglial phagocytosis of glutamatergic synapses and in the pathogenesis of neuroinflammation in Alzheimer’s disease (AD). We recently reported that upregulation of metabotropic glutamate receptor signaling is associated with increased synaptic C1q production and subsequent microglial phagocytosis of synapses in the rodent models of AD. Here, we explored the role of astrocytic glutamate transporter in the synaptic C1q production and microglial phagocytosis of hippocampal glutamatergic synapses in a rat model of AD. Activation of astrocyte and reduction glutamate transporter 1 (GLT1) were noted after bilateral microinjection of amyloid-beta (Aβ1–40) fibrils into the hippocampal CA1 area of rats. Ceftriaxone is a β-lactam antibiotic that upregulates GLT1 expression. Bilateral microinjection of ceftriaxone recovered GLT1 expression, decreased synaptic C1q production, suppressed microglial phagocytosis of glutamatergic synapses in the hippocampal CA1, and attenuated synaptic and cognitive deficits in rats microinjected with Aβ1–40. In contrast, artificial suppression of GLT1 activity by dl-threo-beta-benzyloxyaspartate (DL-TBOA) in naïve rats induced synaptic C1q expression and microglial phagocytosis of glutamatergic synapses in the hippocampal CA1 area, resulting in synaptic and cognitive dysfunction. These findings demonstrated that impairment of astrocytic glutamate transporter plays a role in the pathogenesis of AD.

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Acknowledgments

The authors thank John Peterson, Ph.D., Imaging Core, Cleveland Clinic, for his expertise and help provided for imaging analysis.

Funding

Dr. Naguib is financially supported by the National Institute of Aging of the National Institutes of Health under Award Number R56AG051594. This work utilized the Leica SP8 confocal microscope that was purchased with funding from National Institutes of Health SIG grant1S10OD019972-01.

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  1. Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Ave., Mail Code NB3-78, Cleveland, OH, 44195, USA

    Jiang Wu, Bihua Bie, Joseph F. Foss & Mohamed Naguib

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Wu, J., Bie, B., Foss, J.F. et al. Amyloid Fibril–Induced Astrocytic Glutamate Transporter Disruption Contributes to Complement C1q-Mediated Microglial Pruning of Glutamatergic Synapses. Mol Neurobiol 57, 2290–2300 (2020). https://doi.org/10.1007/s12035-020-01885-7

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