Département de pathologie et biologie cellulaire, Université de Montréal, C.P. 6128, succursale Centre-ville, Montréal, QC H3C 3J7, Canada.
Eur J Neurosci. 2010 Sep;32(6):905-20. doi: 10.1111/j.1460-9568.2010.07379.x. Epub 2010 Aug 19.
Alzheimer's disease (AD) affects cognitive modalities that are known to be regulated by adult neurogenesis, such as hippocampal- and olfactory-dependent learning and memory. However, the relationship between AD-associated pathologies and alterations in adult neurogenesis has remained contentious. In the present study, we performed a detailed investigation of adult neurogenesis in the triple transgenic (3xTg) mouse model of AD, a unique model that generates both amyloid plaques and neurofibrillary tangles, the hallmark pathologies of AD. In both neurogenic niches of the brain, the hippocampal dentate gyrus and forebrain subventricular zone, we found that 3xTg mice had decreased numbers of (i) proliferating cells, (ii) early lineage neural progenitors, and (iii) neuroblasts at middle age (11months old) and old age (18months old). These decreases correlated with major reductions in the addition of new neurons to the respective target areas, the dentate granule cell layer and olfactory bulb. Within the subventricular zone niche, cytological alterations were observed that included a selective loss of subependymal cells and the development of large lipid droplets within the ependyma of 3xTg mice, indicative of metabolic changes. Temporally, there was a marked acceleration of age-related decreases in 3xTg mice, which affected multiple stages of neurogenesis and was clearly apparent prior to the development of amyloid plaques or neurofibrillary tangles. Our findings indicate that AD-associated mutations suppress neurogenesis early during disease development. This suggests that deficits in adult neurogenesis may mediate premature cognitive decline in AD.
阿尔茨海默病（AD）影响已知受成人神经发生调节的认知方式，如海马和嗅觉依赖的学习和记忆。然而，AD 相关病理学与成人神经发生变化之间的关系一直存在争议。在本研究中，我们对 AD 的三转基因（3xTg）小鼠模型中的成年神经发生进行了详细研究，该模型独特地产生淀粉样斑块和神经原纤维缠结，这是 AD 的标志性病理学。在大脑的两个神经发生部位，海马齿状回和前脑脑室下区，我们发现 3xTg 小鼠在中年（11 个月大）和老年（18 个月大）时，（i）增殖细胞、（ii）早期谱系神经祖细胞和（iii）神经母细胞的数量减少。这些减少与新神经元分别向各自靶区（齿状回颗粒细胞层和嗅球）的添加量的主要减少相关。在脑室下区龛位中，观察到细胞学改变，包括室管膜下细胞的选择性丧失和 3xTg 小鼠室管膜内大脂质滴的形成，表明代谢变化。在时间上，3xTg 小鼠的年龄相关减少明显加速，这影响了神经发生的多个阶段，并且在淀粉样斑块或神经原纤维缠结发展之前就很明显。我们的发现表明，AD 相关突变在疾病发展早期抑制神经发生。这表明成年神经发生的缺陷可能介导 AD 中的认知能力过早下降。
