A11 the Temporal and Spatial Appearance of HTT Aggregation in the Brains of Zq175 Mice

Background Huntington-lowering approaches are a major focus for therapeutic intervention for Huntington’s disease. In evaluating these treatments, it will be important to understand how the targeting strategy affects levels of the HTT1a and full-length HTT transcripts and the soluble exon 1 HTT and full-length HTT proteins that they encode. It will also be important to determine how a given strategy impacts on the subcellular location of HTT aggregation, dependent on the stage of disease at which the intervention was administered. Aim Here, we set out to map the earliest ages at which the appearance of HTT aggregation could be detected throughout the brain in heterozygous zQ175 mice. Results Aggregation analyses were performed at monthly intervals from 1-6 months of age. Immunohistochemistry with the S830 antibody detected aggregated HTT in the form of a diffuse nuclear immunostain in neuronal nuclei in the striatum, hippocampus and cortex by 2 months. By 6 months, nuclear and cytoplasmic inclusions were widely distributed throughout the brain. We also applied two HTRF assays to track the accumulation aggregated HTT in eight brain regions; one of which could detect aggregation in the striatum and cortex at one month of age. HTRF showed that soluble exon 1 HTT levels decreased over the 6-month period, whilst levels of soluble full-length mutant HTT remained unchanged. Conclusions These data support the hypothesis, that exon 1 HTT initiates the aggregation process in knock-in mouse models and paves the way for a detailed analysis of HTT aggregation in response to HTT-lowering treatments.