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Chronic pain causes Tau-mediated hippocampal pathology and memory deficits

Molecular Psychiatry volume 27, pages 4385–4393 (2022)Cite this article

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Abstract

Persistent pain has been recently suggested as a risk factor for dementia. Indeed, chronic pain is frequently accompanied by maladaptive brain plasticity and cognitive deficits whose molecular underpinnings are poorly understood. Despite the emerging role of Tau as a key regulator of neuronal plasticity and pathology in diverse brain disorders, the role of Tau has never been studied in the context of chronic pain. Using a peripheral (sciatic) neuropathy to model chronic pain in mice—spared nerve injury (SNI) for 4 months—in wildtype as well as P301L-Tau transgenic mice, we hereby demonstrate that SNI triggers AD-related neuropathology characterized by Tau hyperphosphorylation, accumulation, and aggregation in hippocampus followed by neuronal atrophy and memory deficits. Molecular analysis suggests that SNI inhibits autophagy and reduces levels of the Rab35, a regulator of Tau degradation while overexpression of Rab35 or treatment with the analgesic drug gabapentin reverted the above molecular changes leading to neurostructural and memory recovery. Interestingly, genetic ablation of Tau blocks the establishment of SNI-induced hippocampal morphofunctional deficits supporting the mediating role of Tau in SNI-evoked hippocampal pathology and memory impairment. These findings reveal that exposure to chronic pain triggers Tau-related neuropathology and may be relevant for understanding how chronic pain precipitates memory loss leading to dementia.

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Fig. 1: Chronic neuropathic pain leads to cognitive impairment and neuronal atrophy which are attenuated by the analgesic drug, gabapentin.
Fig. 2: Prolonged neuropathic pain triggers Tau accumulation and inhibition of autophagy in the hippocampus.
Fig. 3: Rab35 overexpression blocked the SNI-evoked Tau accumulation and related memory deficits.
Fig. 4: Tau ablation blocked memory loss and hippocampal atrophy induced by chronic neuropathic pain.

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Acknowledgements

We would like to thank Dr. Peter Davies (Albert Einstein College, USA) for kindly providing us the PHF-1 and DA9 antibodies and Dr. Akihiko Takashima (Gakushuin University, Japan) for JM human Tau antibody. Also, we thank Prof. Clarissa Waites (Columbia University, NY, USA) for the Rab35 virus. This work has been funded by Portuguese national funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298; POCI-01-0145-FEDER-007038) supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Additionally, this work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122); by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). It was also funded by the Foundation for Science and Technology (FCT), under the scope of the project PTDC/NEU-SCC/5301/2014. Researchers were supported by FCT grant numbers: PD/BD/114117/2015 (MRG) and PD/BD/127825/2016 (CD) via Inter-University Doctoral Program in Ageing and Chronic Disease (PhDOC), PD/BD/135271/2017 (PG) via MD-PhD Program. SG integrated the Master Program in Health Sciences of the School of Medicine, University of Minho.

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  1. These authors contributed equally: Hugo Leite-Almeida, Ioannis Sotiropoulos.

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal

    Sara R. Guerreiro, Marco R. Guimarães, Joana M. Silva, Chrysoula Dioli, Raquel Sousa, Patrícia Gomes, Carlos Campos-Marques, Ana Margarida Cunha, Armando Almeida, Nuno Sousa, Hugo Leite-Almeida & Ioannis Sotiropoulos

  2. ICVS/3B’s - PT Government Associate Laboratory, Braga, Guimarães, Portugal

    Sara R. Guerreiro, Marco R. Guimarães, Joana M. Silva, Chrysoula Dioli, Raquel Sousa, Patrícia Gomes, Carlos Campos-Marques, Ana Margarida Cunha, Armando Almeida, Nuno Sousa, Hugo Leite-Almeida & Ioannis Sotiropoulos

  3. Institute of Biosciences and Applications, NCSR Demokritos, Athens, Greece

    Chrysoula Dioli, Anastasia Vamvaka-Iakovou, Anastasia Megalokonomou & Ioannis Sotiropoulos

  4. Medical School, University of Crete, Heraklion, Greece

    Anastasia Megalokonomou

  5. Clinical Academic Center (2CA), Braga, Portugal

    Nuno Sousa

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Contributions

IS, HL-A and NS conceived the project. SRG, MRG, JMS, CD, AV-I, RS, PG, AM, CC-M, AMC, AA, performed experiments and analyzed the data. IS and HL-A supervised the study and wrote the manuscript.

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Correspondence to Hugo Leite-Almeida or Ioannis Sotiropoulos.

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Guerreiro, S.R., Guimarães, M.R., Silva, J.M. et al. Chronic pain causes Tau-mediated hippocampal pathology and memory deficits. Mol Psychiatry 27, 4385–4393 (2022). https://doi.org/10.1038/s41380-022-01707-3

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