Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
J Neurosci Res. 2010 Aug 1;88(10):2103-17. doi: 10.1002/jnr.22387.
Formation of new neurons in the adult brain takes place in the subventricular zone and in the subgranule layer of the dentate gyrus throughout life. Neurogenesis is thought to play a role in hippocampus- and olfaction-dependent learning and memory. However, whether impairments in neurogenesis take place in learning and memory disorders, such as Alzheimer's disease, is yet to be established. Importantly, it remains to be elucidated whether neurogenic impairments play a role in the course of the disease or are the result of extensive neuropathology. We now report that transgenic mice harboring familial Alzheimer's disease-linked mutant APPswe/PS1DeltaE9 exhibit severe impairments in neurogenesis that are evident as early as 2 months of age. These mice exhibit a significant reduction in the proliferation of neural progenitor cells and their neuronal differentiation. Interestingly, levels of hyperphosphorylated tau, the cytotoxic precursor of the Alzheimer's disease hallmark neurofibrillary tangles, are particularly high in the neurogenic niches. Isolation of neural progenitor cells in culture reveals that APPswe/PS1DeltaE9-expressing neurospheres exhibit impaired proliferation and tau hyperphosphorylation compared with wildtype neurospheres isolated from nontransgenic littermates. This study suggests that impaired neurogenesis is an early critical event in the course of Alzheimer's disease that may underlie memory impairments, at least in part, and exacerbate neuronal vulnerability in the hippocampal formation and olfaction circuits. Furthermore, impaired neurogenesis is the result of both intrinsic pathology in neural progenitor cells and extrinsic neuropathology in the neurogenic niches. Finally, hyperphosphorylation of the microtubule-associated protein tau, a critical player in cell proliferation, neuronal maturation, and axonal transport, is a major contributor to impaired neurogenesis in Alzheimer's disease.
成年大脑中的新神经元形成发生在脑室下区和齿状回的颗粒下层，终生都在进行。神经发生被认为在海马体和嗅觉依赖的学习和记忆中发挥作用。然而，在学习和记忆障碍（如阿尔茨海默病）中是否存在神经发生损伤尚待确定。重要的是，仍然需要阐明神经发生损伤是否在疾病过程中起作用，或者是否是广泛神经病理学的结果。我们现在报告，携带家族性阿尔茨海默病相关突变 APPswe/PS1DeltaE9 的转基因小鼠表现出严重的神经发生损伤，早在 2 个月大时就很明显。这些小鼠表现出神经祖细胞增殖和其神经元分化的显著减少。有趣的是，阿尔茨海默病标志性神经纤维缠结的细胞毒性前体过度磷酸化的 tau 水平在神经发生龛中特别高。在培养物中分离神经祖细胞表明，与从非转基因同窝仔中分离的野生型神经球相比，表达 APPswe/PS1DeltaE9 的神经球表现出增殖受损和 tau 过度磷酸化。这项研究表明，神经发生受损是阿尔茨海默病病程中的一个早期关键事件，至少部分导致记忆障碍，并加剧海马体和嗅觉回路中的神经元易损性。此外，神经发生受损是神经祖细胞内在病理学和神经发生龛中外在神经病理学的结果。最后，微管相关蛋白 tau 的过度磷酸化是细胞增殖、神经元成熟和轴突运输的关键参与者，是阿尔茨海默病中神经发生受损的主要原因。
