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Characterization of constitutive caspase-6 deficient mice : insights into axonal degeneration, excitotoxicity and age dependent behavioral and neuroanatomical changes Uribe Laisequilla, Valeria

Abstract

Apoptosis or programmed cell death is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular cysteine-aspartic proteases that play a key role in programmed cell death. Aside from their roles during development, aberrant activation of caspases has been implicated in several human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in depth neuropathological and behavioral characterization of constitutive Casp6-deficient (Casp6 -/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function and to establish if any biological effects are caused by ablation of Casp6. We demonstrate that Casp6 -/- neurons are protected against NMDAmediated excitotoxicity and NGF-deprivation induced axonal degeneration. Furthermore, Casp6 deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6 -/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in Huntington disease and the cortex in Alzheimer Disease. These results provide further insights into the role of Casp6 in neurodegenerative diseases.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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