DIFFERENTIAL SUSCEPTIBILITY OF STRIATAL, HIPPOCAMPAL AND CORTICAL NEURONS TO CASPASE-6

Abstract

Caspase-6 (Casp6), a cysteinyl protease of the caspase family, is activated early in Huntington disease (HD) and thought to contribute to its pathogenesis by generating a toxic fragment of huntingtin (Htt). Active Casp6 and TauΔCasp6 were assessed in 50–70 yr old grade II HD and age-matched control brains by immunohistochemistry with neoepitope antisera against active Casp6 and Tau cleaved by Casp6 (TauΔCasp6). To assess whether Casp6 activity induces HD-like pathogenesis, a transgenic knock-in mouse (ACK) expressing a self-activated form of human Casp6 in the medium spiny neurons of the indirect striatopallidal pathway, the main brain circuit affected in HD, was generated. Occasional intra-nuclear inclusions immunopositive for active Casp6 and TauΔCasp6 were observed in HD, but not in control, striatal neurons. Conversely, inclusions were absent while active Casp6 and TauΔCasp6 immunopositive neurofibrillary tangles were frequent in HD, but rare, in the control hippocampus. Relative to non-transgenic mice, Casp6 protein was increased 5.2, 2.5, and 2.6 fold in the striatum, cortex and hippocampus of the ACK brains, respectively. Detection of Tubulin cleaved by Casp6 (TubΔCasp6) confirmed Casp6 activity. ACK and control littermate mice were subjected to psychiatric, motor, and cognitive behavioral tests. No evidence of depression was evident with the forced swim and sucrose consumption tests. No sensorimotor or locomotor deficits were noticed in the nesting, clasping, rotarod, vertical pole, gait and open field analyses. However, ACK mice developed age-dependent episodic and spatial memory deficits identified by the novel object recognition test and the Barnes or Morris water maze, respectively. Synaptic protein levels and neuron numbers were maintained in the ACK striatum, hippocampus and cortex. Iba1 positive microglia of the phagocytic type 4 and GFAP positive astroglial staining were increased in the ACK hippocampal stratum lacunosum molecular and in the cortex, but not in the striatum. These data suggest that active Casp6 in the striatal medium spiny neurons does not induce HD-like motor deficits or inflammation, whereas active Casp6 in the hippocampus and cortex impairs episodic and spatial memory and increases inflammation. These results reveal neuron specific vulnerability to Casp6 activation.