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Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6

Cell Death & Differentiationvolume 25pages13191335 (2018) | Download Citation


Active cysteinyl protease Caspase-6 is associated with early Alzheimer and Huntington diseases. Higher entorhinal cortex and hippocampal Caspase-6 levels correlate with lower cognitive performance in aged humans. Caspase-6 induces axonal degeneration in human primary neuron cultures and causes inflammation and neurodegeneration in mouse hippocampus, and age-dependent memory impairment. To assess whether Caspase-6 causes damage to another neuronal system, a transgenic knock-in mouse overexpressing a self-activated form of Caspase-6 five-fold in the striatum, the area affected in Huntington disease, and 2.5-fold in the hippocampus and cortex, was generated. Detection of Tubulin cleaved by Caspase-6 confirmed Caspase-6 activity. The Caspase-6 expressing mice and control littermates were subjected to behavioral tests to assess Huntington disease-relevant psychiatric, motor, and cognitive deficits. Depression was excluded with the forced swim and sucrose consumption tests. Motor deficits were absent in the nesting, clasping, rotarod, vertical pole, gait, and open field analyzes. However, Caspase-6 mice developed age-dependent episodic and spatial memory deficits identified by novel object recognition, Barnes maze and Morris water maze assays. Neuron numbers were maintained in the striatum, hippocampus, and cortex. Microglia and astrocytes were increased in the hippocampal stratum lacunosum molecular and in the cortex, but not in the striatum. Synaptic mRNA profiling identified two differentially expressed genes in transgenic hippocampus, but none in striatum. Caspase-6 impaired synaptic transmission and induced neurodegeneration in hippocampal CA1 neurons, but not in striatal medium spiny neurons. These data revealed that active Caspase-6 in the striatal medium spiny neurons failed to induce inflammation, neurodegeneration or behavioral abnormalities, whereas active Caspase-6 in the cortex and hippocampus impaired episodic and spatial memories, and induced inflammation, neuronal dysfunction, and neurodegeneration. The results indicate age and neuronal subtype-dependent Caspase-6 toxicity and highlight the importance of targeting the correct neuronal subtype to identify underlying molecular mechanisms of neurodegenerative diseases.

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We would like to thank the animal quarters staff, especially Véronique Michaud, for maintaining the mice, Dr Joseph Flores for mice perfusions, the IRIC Université de Montréal pathology core for embedding and cutting brain tissue sections, Dr Agne Tubeleviciute-Aydin for the preparation of recombinant Casp6, and Dr Yves De Koninck, Dr Sonia Goulet and Dr François Y Doré (Université Laval, QC) for lending us the rotarod apparatus. The Douglas – Bell Canada Brain Bank is supported by the Quebec Suicide Research Network of the Fonds de Recherche du Québec - Santé (FRQS) and by the Douglas Institute Foundation. We are very grateful to Dr Steffen Albrecht (McGill University, Montreal, QC) for help with the interpretation of the human immunostaining in HD brains, and to Dr David A. Bennett (Rush Medical School, Chicago, Il) for the AD tissues. We thank Christina You Chien Chou, Jennifer Brock, and Elvis Cela for help and guidance with electrophysiology and 2-photon imaging. Anastasia Noël received a postdoctoral scholarship from the Alzheimer Society of Canada. Libin Zhou is a recipient of an Alzheimer Society of Canada Dr and Mrs Spatz doctoral award. This work was supported by funds from the Canadian Institutes of Health Research (CIHR) MOP-243413-BCA-CGAG-45097, and the JGH Foundation to ALB. P.J.S. was funded by CIHR OG 126137, CIHR NIA 288936, NSERC DG 2017-04730, NSERC DAS 2017-507818.

Author information


  1. Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin Côte Ste Catherine, Montreal, QC, H3A 2B4, Canada

    • Anastasia Noël
    • , Libin Zhou
    • , Bénédicte Foveau
    •  & Andréa C. LeBlanc
  2. Department of Neurology and Neurosurgery, McGill University, 3755 University Street, Montreal, QC, H3A 2B4, Canada

    • Anastasia Noël
    • , Libin Zhou
    • , Bénédicte Foveau
    • , P. Jesper Sjöström
    •  & Andréa C. LeBlanc
  3. Department of Anatomy and Cell Biology, McGill University, 3755 University Street, Montreal, QC, H3A 2B4, Canada

    • Libin Zhou
    •  & Andréa C. LeBlanc
  4. Centre for Research in Neuroscience, The BRAIN Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montréal, QC, H3G 1A4, Canada

    • P. Jesper Sjöström


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The authors declare that they have no conflict of interest.

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Correspondence to Andréa C. LeBlanc.

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