There is strong clinical evidence that multifaceted gait abnormalities may be manifested at early stages of Alzheimer’s disease (AD), are related to cognitive decline, and can be used as an early biomarker to identify patients at risk of progressing to full-blown dementia. Despite their importance, gait abnormalities have not been investigated in mouse models of AD, which replicate important aspects of the human disease. The Tg2576 is frequently used in AD research to test therapeutic interventions targeting cellular mechanisms contributing to the genesis of AD. This transgenic mouse strain overexpresses a mutant form of the 695 amino acid isoform of human amyloid precursor protein with K670N and M671L mutations (APPK670/671L) linked to early-onset familial AD. Tg2576 mice exhibit impaired cognitive functions and increased cortical and hippocampal soluble β-amyloid levels starting from 5 months of age and increased insoluble β-amyloid levels and amyloid plaques that resemble senile plaques associated with human AD by 13 months of age. To demonstrate early manifestations of gait dysfunction in this relevant preclinical model, we characterized gait and motor performance in 10-month-old Tg2576 mice and age-matched littermate controls using the semi-automated, highly sensitive, Catwalk XT system. We found that Tg2576 mice at the pre-plaque stage exhibited significantly altered duty cycle and step patterns and decreased stride length and stride time. Base-of-support, stride time variability, stride length variability, cadence, phase dispersions and gait symmetry indices were unaltered. The presence of measurable early gait abnormalities during the pre-plaque stages of AD in this relevant preclinical mouse model has direct translational relevance and supports the view that longitudinal monitoring of gait performance could be used in addition to behavioral testing to evaluate progression of the disease and to assess treatment efficacy.

有强有力的临床证据表明，多方面的步态异常可能出现在阿尔茨海默病 (AD) 的早期阶段，与认知能力下降有关，并且可以用作早期生物标志物来识别有进展为全面痴呆风险的患者。尽管步态异常很重要，但尚未在 AD 小鼠模型中进行研究，该模型复制了人类疾病的重要方面。Tg2576 经常用于 AD 研究，以测试针对导致 AD 发生的细胞机制的治疗干预措施。这种转基因小鼠品系过度表达人类淀粉样前体蛋白的 695 个氨基酸亚型的突变形式，其 K670N 和 M671L 突变 (APPK670/671L) 与早发家族性 AD 相关。Tg2576 小鼠从 5 个月大开始表现出认知功能受损，皮质和海马可溶性 β-淀粉样蛋白水平增加，到 13 个月大时，不溶性 β-淀粉样蛋白水平和淀粉样斑块增加，类似于与人类 AD 相关的老年斑。为了证明该相关临床前模型中步态功能障碍的早期表现，我们使用半自动、高度灵敏的 Catwalk XT 系统对 10 个月大的 Tg2576 小鼠和年龄匹配的同窝小鼠的步态和运动表现进行了表征。我们发现，斑块前阶段的 Tg2576 小鼠表现出显着改变的占空比和步态模式，以及步幅长度和步幅时间的缩短。支撑基础、步幅时间变异性、步幅长度变异性、节奏、相位分散和步态对称性指数均未改变。在这种相关的临床前小鼠模型中，AD 斑块前阶段存在可测量的早期步态异常，具有直接的转化相关性，并支持这样的观点：除了行为测试之外，还可以使用步态表现的纵向监测来评估疾病的进展和来评估治疗效果。