Localization of mutant huntingtin with HTT Exon1 P90 C-terminal neoepitope antibodies in relation to regional and neuronal vulnerability in forebrain in Q175 mice and human huntington's disease.

Abstract

BackgroundRecent evidence suggests that accumulation of mutant exon 1 protein (HTT1a) may be critical to HD pathogenesis, but the relation of this to differential regional and cellular vulnerability in HD is unknown.ObjectiveWe assessed the contribution of the accumulation of the mutant huntingtin HTT1a to the regional and cellular variation in HD brain pathology by determining if more vulnerable regions and neuron types were relatively enriched.MethodsWe performed immunolabeling using the novel monoclonal antibodies 11G2 and 1B12 against the C-terminal proline 90 (P90) neoepitope of huntingtin HTT1a, which detect accumulation of monomeric, oligomeric and aggregated mutant HTT1a, on forebrain of Q175 and R6/2 mice and human HD cases.ResultsDiffuse nuclear and aggregate immunolabeling increased in abundance in Q175 with age, with striatal projection neurons showing immunolabeling earlier than cortical neurons, and only neuropil immunolabeling prominent in pallidal regions. Nonetheless, some regions less affected in HD, such as hippocampus, were rich in mutant HTT1a as well. In humans, striatal immunolabeling was sparser than in mouse, and mainly in the neuropil, but sparser in striatal target areas. In human HD cortex, the P90 antibodies detected predominantly neuropil aggregates, which appeared to, in part, localize to dendrites. Immunostaining in mouse and human could be blocked with HTT1a target peptide, demonstrating antibody specificity.ConclusionsOur results indicate that mutant HTT1a burden appears to partly account for overall differential forebrain regional vulnerability in HD, but additional factors may contribute to vulnerability differences among forebrain regions and between specific neuron types.