Computational Brain Anatomy Laboratory (CoBrA Lab), Cerebral Imaging Centre, Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montreal, QC, H4H 1R3, Canada.
Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Brain Struct Funct. 2018 Sep;223(7):3365-3382. doi: 10.1007/s00429-018-1691-4. Epub 2018 Jun 13.
Animal models of Alzheimer's disease (AD) can be used to determine the progressive neurodegeneration characteristics of AD in vivo using magnetic resonance imaging (MRI). Given the need for therapeutic interventions before the onset of frank AD, it is critical to examine if AD models demonstrate neuroanatomical remodeling in an equivalent preclinical phase. This manuscript examines the trajectories of brain and behavioural changes in the Triple transgenic mouse model (3xTg) prior to the development of AD-like behaviours. The 3xTg mimics both β-amyloid plaques and neurofibrillary tangles through three mutations associated with familial AD, namely: PS1, APP, and tau transgenes. We performed detailed investigation using longitudinal structural MRI at 6, 8, 12, 16, 20, and 24 weeks old to assess neuroanatomical changes using volumetric and deformation-based analyses. Learning- and memory-related behaviour were assessed through the Morris water maze at 9, 17, and 25 weeks of age. There was the absence of major memory deficits with the notable exception of water maze conducted at 17 weeks old, where 3xTg group spent significantly less time in the quadrant of interest in the probe trial. Through volumetric and deformation-based analyses, we observed relative decrease over time in the 3xTg group in the third ventricle, piriform cortex, fornix, and fimbria relative to the control group. We also observed decreases over time in the control mice in the hippocampus, entorhinal cortex, cerebellum, and olfactory bulb. In many of these cases, we note a delay in the attainment of peak volume in the 3xTgs relative to the control group, suggesting a possible neurodevelopmental and maturational delay given the likely over-expression of AD-related pathology from birth. Importantly, neuroanatomical alterations are observed prior to the manifestation of AD-like behaviours, suggesting that mutated amyloid and tau are, indeed, sufficient to cause changes in the neuroanatomy in 3xTg mice, but potentially insufficient to be responsible for behavioural changes in the earlier stages of life.
阿尔茨海默病（AD）的动物模型可用于通过磁共振成像（MRI）在体内确定 AD 的进行性神经退行性变特征。鉴于需要在出现明显 AD 之前进行治疗干预，因此检查 AD 模型是否在等效的临床前阶段表现出神经解剖重塑至关重要。本文研究了三转基因小鼠模型（3xTg）在出现类似 AD 的行为之前大脑和行为变化的轨迹。该 3xTg 通过与家族性 AD 相关的三个突变（PS1、APP 和 tau 转基因）模拟了β-淀粉样斑块和神经原纤维缠结。我们使用纵向结构 MRI 在 6、8、12、16、20 和 24 周龄时进行了详细的研究，以使用基于体积和变形的分析评估神经解剖变化。通过 Morris 水迷宫在 9、17 和 25 周龄时评估学习和记忆相关行为。3xTg 组在水迷宫测试中除了在 17 周龄的水迷宫测试中表现出明显的记忆缺陷外，在其他测试中均未表现出主要的记忆缺陷。3xTg 组在探针试验中在感兴趣的象限中花费的时间明显减少。通过基于体积和变形的分析，我们观察到 3xTg 组随着时间的推移，第三脑室、梨状皮质、穹窿和终纹相对于对照组相对减少。我们还观察到随着时间的推移，对照组小鼠的海马体、内嗅皮质、小脑和嗅球体积减少。在许多情况下，我们注意到 3xTg 相对于对照组达到峰值体积的时间延迟，这表明由于 AD 相关病理的过度表达，可能存在神经发育和成熟延迟。重要的是，在出现类似 AD 的行为之前观察到神经解剖变化，这表明突变的淀粉样蛋白和 tau 确实足以导致 3xTg 小鼠的神经解剖结构发生变化，但在生命的早期阶段可能不足以导致行为变化。
