Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice.

Abstract We studied the development of neuronal intranuclear inclusions (NIIs), neuropil aggregates (NAs), and expression of expanded repeat polyglutamine protein in the Hdh CAG(150) knockin mouse model of Huntington’s disease (HD). Diffuse nuclear localization of huntingtin protein (htt) was noted initially within striatal neurons at approximately 28 weeks, followed by the development of striatal htt immunoreactive NIIs by approximately 40 weeks. Striatal NIIs were observed initially in clusters within the matrix compartment but subsequently became diffusely distributed throughout the striatum. In the oldest animals (107 weeks), NIIs were enlarged and diffuse nuclear htt immunoreactivity reduced. Expression of ubiquitin immunoreactive NIIs paralleled but lagged behind the expression of htt immunoreactive NIIs. Abundant NIIs were found by approximately 75 weeks in layers 3 and 4 of somatosensory cortex and in layer 2 of piriform cortex. In the oldest animals, greater than 100 weeks, some NIIs were found in many brain regions. NAs were found mainly within the globus pallidus and substantia nigra, perhaps reflecting expression in striatal terminals. Cyclic AMP response element binding protein (CBP) was not localized to NIIs, arguing against gross sequestration of this transcriptionally active protein. Comparison of the relative levels of a common polyglutamine epitope in Hdh CAG(150) knockin and hprt CAG(146) knockin mice shows greater expression of the polyglutamine epitope in the phenotypically less aggressive Hdh CAG(150) knockin line. Hdh CAG(150) knockin mice may be a model of early pathologic changes in HD.