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.