Light and electron microscopic characterization of the evolution of cellular pathology in YAC128 Huntington's disease transgenic mice

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disease caused by the insertion of an expanded polyglutamine sequence within the huntingtin protein. This mutation induces the formation of abnormal protein fragment aggregations and intra-nuclear neuronal inclusions in the brain. The present study aimed to produce a detailed longitudinal characterization of the neuronal pathology in the YAC128 transgenic mouse brain, to determine the similarity of this mouse model to other mouse models and the human condition in the spatial and temporal deposition pattern of the mutant protein fragments. Brain samples were taken from mice aged between 4 and 27 months of age, and assessed using S830 and GFAP immunohistochemistry, stereology and electron microscopy. Four month old mice did not exhibit intra-nuclear or extra-nuclear inclusions using the S830 antibody. Diffuse nuclear staining was present in the cortex, hippocampus and cerebellum from 6 months of age onwards. By 15 months of age, intra-nuclear inclusions were visible in most brain regions including nucleus accumbens, ventral striatum, lateral striatum, motor cortex, sensory cortex and cerebellum. The ventral striatum had a greater density of inclusions than the dorsal striatum. At 15 and 24 months of age, the mice showed increased reactive astrogliosis in the cortex, but no differences were found in the striatum. Necrotic cell death with vacuolation, uneven cell membrane and degenerated Golgi apparatus were detected ultrastructurally at 14 months of age, with some cells showing signs of apoptosis. By 26 months of age, most cells were degenerated in the transgenic animals, with lipofuscin granules being more abundant and larger in these mice than in their wildtype littermates. Our results demonstrate a progressive and widespread neuropathology in the YAC128 mice line that shares some similarity to the human condition. This article is part of a Special Issue entitled 'HD Transgenic Mouse'.