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Blockade of Type 2A Protein Phosphatase Signaling Attenuates Complement C1q-Mediated Microglial Phagocytosis of Glutamatergic Synapses Induced by Amyloid Fibrils

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Abstract

We previously reported the critical involvement of metabotropic GluR1 (mGluR1) signaling in complement C1q-dependent microglial phagocytosis of glutamatergic synapses in a rat model of Alzheimer’s disease (AD) injected with amyloid fibrils. Here, we explored the role of type 2A protein phosphatase (type 2A PPase), a key enzyme downstream of mGluR1 signaling, in the pathogenesis of AD in rats. Significant local upregulation of PP2A expression was observed in the hippocampal CA1 after bilateral microinjection of amyloid-beta (Aβ1-40) fibrils. Amyloid fibrils induced remarkable dephosphorylation of pFMRP (fragile X mental retardation protein) and C1q upregulation in hippocampal glutamatergic synapses, which was ameliorated by microinjection of type 2A PPase inhibitor okadaic acid (OA). Microinjection of OA further attenuated the microglial phagocytosis of glutamatergic synapses, recovered the hippocampal glutamatergic transmission, and improved the performance in Morris water maze test. These findings demonstrated that dysfunction of type 2A PPase signaling contributed to complement C1q-dependent microglial phagocytosis of glutamatergic synapses and the cognitive impairments in the rat model of AD.

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Data Availability

The original dataset for analysis in the present study is available upon reasonable request from the corresponding author.

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Funding

Dr. Naguib was supported by the National Institute of Aging of the National Institutes of Health under Award Number R56AG051594. Dr. Xu is supported by NIH K08CA228039.

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Authors and Affiliations

  1. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Jiang Wu, Mohamed Naguib & Bihua Bie

  2. Department of Pain Management, Anesthesiology Institute, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Jijun Xu

  3. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Jijun Xu

  4. Department of Biomedical Engineering, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Bihua Bie

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Contributions

Bihua Bie, conceptualization, methodology, data curation, original draft, and final review. Jiang Wu, methodology, data curation, and analysis. Mohamed Naguib, conceptualization, data analysis, validation and supervision, and original draft and review. Jijun Xu, data analysis and writing — review and editing.

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Correspondence to Bihua Bie.

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All animal procedures were approved by Institutional Committee of Animal Care and Use in Cleveland Clinic under the protocol number 2016–1662.

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Not applicable. This study does not involve any human subjects.

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The authors declare no competing interests. Dr. Xu is a consultant to Genentech.

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Wu, J., Xu, J., Naguib, M. et al. Blockade of Type 2A Protein Phosphatase Signaling Attenuates Complement C1q-Mediated Microglial Phagocytosis of Glutamatergic Synapses Induced by Amyloid Fibrils. Mol Neurobiol 60, 1527–1536 (2023). https://doi.org/10.1007/s12035-022-03161-2

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