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Updated: May 13, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Absence of hippocampal pathology persists in the Q175DN mouse model of Huntington's disease despite elevated HTT
Melissa A Solem1, Ross G Pelzel1, Nicholas B Rozema1
1Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
Insights
Huntington's disease (HD) mouse models show differing neuropathology. Q175DN mice exhibit enhanced mutant huntingtin (mHTT) aggregation but lack hippocampal degeneration, unlike striatal neurons.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder primarily affecting the striatum.
- The role of other brain regions, like the hippocampus, in HD pathogenesis is less understood.
Purpose of the Study:
- To comparatively analyze the impact of enhanced mutant huntingtin (mHTT) aggregation and neuropathology in the striatum and hippocampus of two HD mouse models.
- To investigate differences in mHTT toxicity susceptibility between striatal and hippocampal neurons.
Main Methods:
- Utilized zQ175 (control) and Q175DN (enhanced mHTT aggregation) HD mouse models.
- Assessed HTT aggregation, neuronal/glial pathology, chaperone expression, and synaptic density in striatum and hippocampus.
- Compared neuropathology between the two mouse models.
Main Results:
- Q175DN mice showed increased mHTT aggregation in both striatum and hippocampus compared to zQ175 mice.
- Striatal neurons were more susceptible to mHTT accumulation in Q175DN mice.
- Despite higher mHTT levels, Q175DN mice showed no hippocampal pathology, increased synaptic density, and altered microglia/HSF1 levels in the hippocampus.
Conclusions:
- Q175DN mice are valuable for studying differential susceptibility to mHTT toxicity between brain regions.
- Cognitive deficits in HD may stem from striatal dysfunction or other brain areas, not necessarily hippocampal degeneration.
Abstract:
BackgroundHuntington's disease (HD) is a neurodegenerative disorder causing motor, cognitive, and psychiatric impairments, with the striatum being the most affected brain region. However, the role of other regions, such as the hippocampus, in HD remains less understood.ObjectiveHere, we study the comparative impact of enhanced mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models.MethodsWe utilized the zQ175 as a control HD mouse model and the Q175DN mice lacking the PGK-Neomycin cassette generated in house. We performed a comparative characterization of the neuropathology between zQ175 and Q175DN mice in the striatum and the hippocampus by assessing HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density.ResultsWe showed that Q175DN mice presented enhanced mHTT aggregation in both striatum and hippocampus compared to zQ175. Striatal neurons showed a greater susceptibility to enhanced accumulation of mHTT in Q175DN. On the contrary, no signs of hippocampal pathology were found in zQ175 and absence of hippocampal pathology persisted in Q175DN mice despite higher levels of mHTT. In addition, Q175DN hippocampus presented increased synaptic density, decreased Iba1+ microglia density and enhanced HSF1 levels in specific subregions of the hippocampus compared to zQ175.ConclusionsQ175DN mice are a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between striatal neurons and other neuronal subtypes. Furthermore, our findings also suggest that cognitive deficits observed in HD animals might arise from either striatum dysfunction or other regions involved in cognitive processes but not from hippocampal degeneration.
