Development of cognitive, motor, metabolic, and mutant huntingtin aggregation in the zQ175 mouse model of Huntington’s disease

McLean, Fiona H., Monteiro, Olivia, Lelos, Mariah J. ORCID: https://orcid.org/0000-0001-7102-055X, Ekkunagul, Thanapon, Spicer, Rachel M., Rybnicek, Jonas, Lambert, Jeremy J. and Langston, Rosamund F. 2025. Development of cognitive, motor, metabolic, and mutant huntingtin aggregation in the zQ175 mouse model of Huntington’s disease. Scientific Reports 15 (1) , 34563. 10.1038/s41598-025-17956-5

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Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disease. In humans, the clinical diagnosis is often dependent on the emergence of motor symptoms. However, cognitive impairments and metabolic changes can be early indicators. HD mouse models are a useful tool to understand disease progression, however, relatively few studies have monitored the timeline for the emergence of cognitive indices with motor and metabolic phenotypes in parallel. In this study, cognitive, motor, and metabolic phenotypes were investigated at different ages in the zQ175 knock-in mouse alongside immunohistochemical and long-term potentiation (LTP) studies. We demonstrated that zQ175 mice developed impaired hippocampal LTP at 3-months and cognitive deficits in visuospatial attention were evident by 4-months. Long-term and spatial memory impairments emerged by 12-months, alongside motor impairments. Additionally, an anxiolytic-like phenotype emerged at 6-months. Differences in body weight were also detected from 6-months onwards, primarily driven by a reduction in fat mass. Additionally, reduced brain weight and the presence of huntingtin aggregates in the hippocampus, striatum and hypothalamus were observed at 12-months. These data support the zQ175 mouse as a model of HD, which recapitulates many aspects of the disease progression in humans and can be used to understand mechanisms underlying the disease.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2045-2322
Date of First Compliant Deposit:	10 October 2025
Date of Acceptance:	28 August 2025
Last Modified:	10 Oct 2025 14:59
URI:	https://orca.cardiff.ac.uk/id/eprint/181589

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