Enhanced Hippocampal Spare Capacity in Q175DN Mice Despite Elevated mHTT Aggregation

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder impacting motor, cognitive, and psychiatric functions.
• The striatum is primarily affected in HD, but the hippocampus's role is less understood.
• Investigating differential neuropathology in HD is crucial for understanding disease progression.

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 characterize neuropathological differences between zQ175 and Q175DN HD mouse models.

Main Methods:

• Utilized zQ175 (control) and Q175DN (in-house generated) HD mouse models.
• Assessed HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density in the striatum and hippocampus.
• Performed comparative neuropathological characterization between the two mouse models.

Main Results:

• Q175DN mice exhibited increased mHTT aggregation in both striatum and hippocampus compared to zQ175 mice.
• Striatal neurons demonstrated higher susceptibility to mHTT accumulation than hippocampal neurons in Q175DN mice.
• The hippocampus in Q175DN mice showed increased synaptic density, reduced microglia density, and elevated HSF1 levels, indicating enhanced spare capacity.

Conclusions:

• Q175DN mice serve as a valuable model for studying neuronal susceptibility differences to mHTT toxicity.
• Cognitive deficits in HD may stem from striatal dysfunction rather than hippocampal degeneration.
• Findings highlight region-specific neuropathology in Huntington's disease progression.