Yeung S T, Myczek K, Kang A P, Chabrier M A, Baglietto-Vargas D, Laferla F M
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697-4545, USA.
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697-4545, USA.
Neuroscience. 2014 Feb 14;259:214-22. doi: 10.1016/j.neuroscience.2013.11.054. Epub 2013 Dec 4.
Neuronal loss is the most common and critical feature of a spectrum of brain traumas and neurodegenerative disorders such as Alzheimer's disease (AD). The capacity to generate new neurons in the central nervous system diminishes early during brain development and is restricted mainly to two brain areas in the mature brain: subventricular zone and subgranular zone. Extensive research on the impact of brain injury on endogenous neurogenesis and cognition has been conducted primarily using young animals, when neurogenesis is most active. However, a critical question remains to elucidate the effect of brain injury on endogenous neurogenesis and cognition in older animals, which is far more relevant for age-related neurodegenerative disorders such as AD. Therefore, we examined the impact of neuronal loss on endogenous neurogenesis in aged animals using CaM/Tet-DTA mice, a transgenic model of hippocampal cell loss. Additionally, we investigated whether the upregulation of adult neurogenesis could mitigate cognitive deficits following substantial hippocampal neuronal loss. Our findings demonstrate that aged CaM/Tet-DTA mice that sustain severe neuronal loss exhibit an upregulation of endogenous neurogenesis. However, despite this significant upregulation, neurogenesis alone is not able to mitigate the cognitive deficits observed. Our studies suggest that the aged brain has the capacity to stimulate neurogenesis post-injury; however, multiple therapeutic approaches, including upregulation of endogenous neurogenesis, will be necessary to recover brain function after severe neurodegeneration.
神经元丢失是一系列脑外伤和神经退行性疾病（如阿尔茨海默病（AD））最常见且关键的特征。在脑发育早期，中枢神经系统中产生新神经元的能力就开始下降，并且在成熟大脑中主要局限于两个脑区：脑室下区和颗粒下区。关于脑损伤对内源性神经发生和认知影响的广泛研究主要是在幼龄动物身上进行的，因为此时神经发生最为活跃。然而，一个关键问题仍有待阐明，即脑损伤对老年动物内源性神经发生和认知的影响，而这对于诸如AD等与年龄相关的神经退行性疾病更为相关。因此，我们使用CaM/Tet-DTA小鼠（一种海马体细胞丢失的转基因模型）研究了老年动物中神经元丢失对内源性神经发生的影响。此外，我们还研究了成年神经发生的上调是否能够减轻大量海马神经元丢失后的认知缺陷。我们的研究结果表明，遭受严重神经元丢失的老年CaM/Tet-DTA小鼠表现出内源性神经发生的上调。然而，尽管有这种显著的上调，仅神经发生并不能减轻所观察到的认知缺陷。我们的研究表明，老年大脑在损伤后有刺激神经发生的能力；然而，要在严重神经退行性变后恢复脑功能，包括上调内源性神经发生在内的多种治疗方法将是必要的。
