Affiliations: [a] Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA
| [b] Department of Zoology-Physiology, University of Wyoming, Laramie, WY, USA
| [c] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
Correspondence to: Jonathan H. Fox, Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Tel.: +1 307 766 9953; Fax: +1 307 721 2051; E-mail: email@example.com.
Abstract: Background: Huntington’s disease (HD) is an autosomal dominant disorder caused by a CAG expansion in the huntingtin gene that results in expression of mutant huntingtin protein. Iron accumulates in HD brain neurons. Amyloid precursor protein (APP) promotes neuronal iron export. However, the role of APP in brain iron accumulation in HD is unclear. Objective: To determine the effects of APP insufficiency on HD in YAC128 mice. Methods: We crossed APP hemizygous mice (APP+/-) with YAC128 mice that are transgenic (Tg) for human mutant huntingtin (hmHTT) to generate APP+/+ hmHTT-/-, APP+/- hmHTT-/-, APP+/+ hmHTT+/- and APP+/- hmHTT+/- progeny. Mice were evaluated for behavioral, biochemical and neuropathology HD outcomes at 2–12 months of age. Results: APP heterozygosity decreased cortical APP 25% and 60% in non-Tg and Tg mice, respectively. Cerebral and striatal iron levels were increased by APP knockdown in Tg mice only. Nest-building behavior was decreased in Tg mice; APP knockdown decreased nest building in non-Tg but not Tg mice. Rota-rod endurance was decreased in Tg mice. APP+/- hHTT+/- mice demonstrated additional decreases in rota-rod endurance from 4–10 months of age. Tg mice had smaller striatal volumes and fewer striatal neurons but were not affected by APP knockdown. Conclusions: APP heterozygosity results in greater decreases of cortical APP in Tg versus non-Tg mice. Mutant huntingtin transgenic mice develop brain iron accumulation as a result of greater suppression of APP levels. Elevated brain iron in Tg mice was associated with a decline in motor endurance consistent with a disease promoting effect of iron in the YAC128 model of human HD.
Keywords: Huntington’s disease, neurodegeneration, iron, amyloid precursor protein