Adult neurogenesis and Alzheimer's disease Alzheimer's disease (AD) pathology destroys neurons and synapses in the brain, leading to dementia. The brain generates new neurons throughout life in the hippocampus, a process called adult hippocampal neurogenesis (AHN). Choi et al. found that blocking AHN exacerbated cognitive impairment in an AD mouse model (see the Perspective by Spires-Jones and Ritchie). Inducing neurogenesis alone did not improve cognition in AD mice, whereas inducing neurogenesis while simultaneously ameliorating the neuronal environment via exercise did. The use of genetic or pharmacological treatments that simultaneously induced neurogenesis and increased levels of brain-derived neurotrophic factor (BDNF) mimicked the benefits of exercise on cognition. Thus, inducing both neurogenesis and providing BDNF may be useful as an AD therapeutic. Science, this issue p. eaan8821; see also p. 975 Adult neurogenesis plays a critical role in neurodegeneration and cognition in a mouse model of Alzheimer’s disease. INTRODUCTION Alzheimer’s disease (AD) is the most common form of age-related dementia, characterized by cognitive impairment, neurodegeneration, β-amyloid (Aβ) deposition, neurofibrillary tangle formation, and neuroinflammation. The most popular therapeutic approach aimed at reducing Aβ burden has not yet proved effective in halting disease progression. A successful therapy would both remove the pathological hallmarks of the disease and provide some functional recovery. The hippocampus contains neural progenitor cells that continue to generate new neurons, a process called adult hippocampal neurogenesis (AHN). AHN is impaired before the onset of classical AD pathology in AD mouse models. Human AHN has also been reported to be altered in AD patients. However, evidence supporting a role for AHN in AD has remained sparse and inconclusive. RATIONALE Two fundamental questions remain: (i) whether AHN could be enhanced and exploited for therapeutic purposes for AD, and (ii) whether AHN impairment mediates aspects of AD pathogenesis. To address these questions, we increased AHN genetically (WNT3) and pharmacologically (P7C3) in AD transgenic 5×FAD mice and explored whether promoting AHN alone can ameliorate AD pathology and behavioral symptoms. We assessed the role of exercise, a known neurogenic stimulus, and explored whether promoting AHN in conjunction with the salutary biochemical changes induced by exercise can improve AD pathology and behavioral symptoms in mice. We also investigated whether AHN suppression, by irradiation, temozolomide, or dominant-negative WNT, contributes to AD pathogenesis and assessed the functional roles of AHN in AD. RESULTS Inducing AHN alone conferred minimal to no benefit for improving cognition in 5×FAD mice. Exercise-induced AHN improved cognition along with reduced Aβ load and increased levels of brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), fibronectin type III domain–containing protein–5 (FNDC5), and synaptic markers. However, AHN activation was also required for exercise-induced improvement in memory. Inducing AHN genetically and pharmacologically in combination with elevating BDNF levels mimicked beneficial effects of exercise on AD mice. Conversely, suppressing AHN in early stages of AD exacerbated neuronal vulnerability in later stages of AD, leading to cognitive impairment and increased neuronal loss. However, no such effects from AHN ablation were observed in nontransgenic wild-type (WT) mice, suggesting that AHN has a specific role in AD. CONCLUSION Promoting AHN can only ameliorate AD pathology and cognitive deficits in the presence of a healthier, improved local brain environment, e.g., stimulated by exercise. Increasing AHN alone combined with overexpression of BDNF could mimic exercise-induced improvements in cognition, without reducing Aβ burden. Adult-born neurons generated very early in life are critical for maintaining hippocampal neuronal populations in the hostile brain environment created by AD later in life. Thus, AHN impairment may be a primary event that later mediates other aspects of AD pathogenesis. Future attempts to create pharmacological mimetics of the benefits of exercise on both increased AHN and BDNF may someday provide an effective means for improving cognition in AD. Moreover, increasing neurogenesis in the earliest stages of AD pathogenesis may protect against neuronal cell death later in the disease, providing a potentially powerful disease-modifying treatment strategy for AD. Role of adult-born neurons in AD. Inducing AHN alone by WNT3 and P7C3 together did not prevent cognitive dysfunction, whereas activating AHN through exercise improved memory in 5×FAD mice. Increasing AHN alone together with overexpression of BDNF could mimic exercise-induced improvement in cognition. Suppressing AHN exacerbated neuronal vulnerability, leading to cognitive impairment and increased neuronal loss in 5×FAD mice, but not in WT mice. Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

中文翻译：

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成人神经发生和 BDNF 联合模拟运动对阿尔茨海默病小鼠模型认知的影响

成人神经发生和阿尔茨海默病 阿尔茨海默病 (AD) 病理会破坏大脑中的神经元和突触，导致痴呆。大脑在整个生命过程中都会在海马中生成新的神经元，这一过程称为成人海马神经发生 (AHN)。崔等人。发现阻断 AHN 会加剧 AD 小鼠模型中的认知障碍（参见 Spires-Jones 和 Ritchie 的观点）。单独诱导神经发生并不能改善 AD 小鼠的认知，而在通过运动改善神经元环境的同时诱导神经发生可以。使用同时诱导神经发生和脑源性神经营养因子 (BDNF) 水平增加的遗传或药物治疗模拟了运动对认知的益处。因此，诱导神经发生和提供 BDNF 可用作 AD 治疗剂。科学，这个问题 p。eaan8821; 另见第。975 成人神经发生在阿尔茨海默病小鼠模型的神经变性和认知中起着关键作用。引言 阿尔茨海默病 (AD) 是与年龄相关的痴呆症的最常见形式，其特征是认知障碍、神经变性、β-淀粉样蛋白 (Aβ) 沉积、神经原纤维缠结形成和神经炎症。旨在减少 Aβ 负担的最流行的治疗方法尚未证明可有效阻止疾病进展。成功的治疗将消除疾病的病理特征并提供一些功能恢复。海马体含有神经祖细胞，可以继续产生新的神经元，一个称为成人海马神经发生 (AHN) 的过程。在 AD 小鼠模型中，在经典 AD 病理发生之前，AHN 受损。据报道，人类 AHN 在 AD 患者中也发生了改变。然而，支持 AHN 在 AD 中的作用的证据仍然很少且没有定论。基本原理仍然存在两个基本问题：(i) AHN 是否可以增强和用于 AD 的治疗目的，以及 (ii) AHN 损伤是否介导 AD 发病机制的各个方面。为了解决这些问题，我们在 AD 转基因 5×FAD 小鼠中通过遗传（WNT3）和药理学（P7C3）增加了 AHN，并探讨了单独促进 AHN 是否可以改善 AD 病理和行为症状。我们评估了运动的作用，一种已知的神经源性刺激，并探讨促进AHN结合运动引起的有益生化变化是否可以改善小鼠的AD病理和行为症状。我们还研究了通过辐射、替莫唑胺或显性负性 WNT 抑制 AHN 是否有助于 AD 发病机制，并评估了 AHN 在 AD 中的功能作用。结果 单独诱导 AHN 对改善 5×FAD 小鼠认知的益处很小或没有益处。运动诱发的 AHN 改善认知，同时减少 Aβ 负荷，增加脑源性神经营养因子 (BDNF)、白细胞介素-6 (IL-6)、含纤连蛋白 III 型结构域的蛋白 5 (FNDC5) 和突触标记物的水平。然而，运动诱发的记忆改善也需要 AHN 激活。在遗传和药理学上诱导 AHN 与提高 BDNF 水平相结合，模拟了运动对 AD 小鼠的有益影响。相反，在 AD 早期抑制 AHN 会加剧 AD 后期的神经元脆弱性，导致认知障碍和神经元丢失增加。然而，在非转基因野生型 (WT) 小鼠中未观察到来自 AHN 消融的此类影响，这表明 AHN 在 AD 中具有特定作用。结论 促进 AHN 只能在存在更健康、改善的局部大脑环境（例如，通过运动刺激）的情况下改善 AD 病理和认知缺陷。单独增加 AHN 结合 BDNF 的过表达可以模拟运动诱导的认知改善，而不会减少 Aβ 负担。在生命早期产生的成年出生神经元对于在生命后期由 AD 创造的敌对大脑环境中维持海马神经元群至关重要。因此，AHN 损伤可能是后来介导 AD 发病机制其他方面的主要事件。未来尝试创造运动对 AHN 和 BDNF 增加的益处的药理学模拟物，可能有一天会提供一种有效的方法来改善 AD 的认知。此外，在 AD 发病的早期阶段增加神经发生可以防止疾病后期的神经元细胞死亡，为 AD 提供一种潜在的强大的疾病修饰治疗策略。成人出生神经元在 AD 中的作用。通过 WNT3 和 P7C3 单独诱导 AHN 并不能预防认知功能障碍，而通过运动激活 AHN 可以改善 5×FAD 小鼠的记忆力。单独增加 AHN 和 BDNF 的过度表达可以模拟运动诱导的认知改善。抑制 AHN 会加剧神经元脆弱性，导致 5×FAD 小鼠的认知障碍和神经元丢失增加，但在 WT 小鼠中则不然。成人海马神经发生 (AHN) 在阿尔茨海默病 (AD) 病理学发病之前受损。我们发现运动通过诱导 AHN 和提高脑源性神经营养因子 (BDNF) 的水平，为 AD 小鼠模型 5×FAD 小鼠提供认知益处。在没有增加 AHN 的情况下，单独刺激 AHN 或锻炼都不能改善认知。我们通过遗传和药理学诱导 AHN 并提高 BDNF 水平，成功模拟了运动对 AD 小鼠的有益影响。后来抑制 AHN 导致认知能力恶化和先前存在的齿状神经元丢失。因此，运动的药理学模拟物，增强 AHN 和提高 BDNF 水平，可能会改善 AD 的认知。此外，应用在 AD 的早期阶段，这些模拟物可以防止随后的神经元细胞死亡。