Science：前沿！成人神经细胞再生与BDNF的共操作可作为阿尔兹海默症(AD)的一种强有力治疗途径

阿尔兹海默症（AD，俗称老年痴呆症）是最常见的与年龄相关的痴呆症，其特征包括认知障碍、神经退化、β-淀粉样蛋白（Aβ）的沉积、神经原纤维缠结的形成、以及神经炎症等【1】。

虽然减少Aβ沉积是AD最常见的治疗途径，但是，在阻止AD恶化过程中仍没有被证明是有效的。期待有一种成功的治疗方法，既能消除AD的病理特征，又能实现功能性恢复。

海马体（hippocampus）中包含神经前体细胞（neural progenitor cells），而神经前体细胞能继续产生新的神经元，这一过程被称为成人海马体神经发生（adult hippocampal neurogenesis，AHN）【2】。

已有研究证实，在AD小鼠模型中，当小鼠表现出典型的AD病理学特征，如Aβ聚集等时，AHN已经受到损伤了【3】。在对AD患者的研究中，也发现了AHN类似的变化【4-6】。

尽管在生理条件下，成人产生的神经元在学习和记忆过程中具有重要作用，但是，如在AD等疾病的病理条件下，它们的功能是未知的。

2018年9月7日，来自美国哈佛医学院马萨诸塞州综合医院、美国索尔克生物研究所、美国佛罗里达大西洋大学脑研究所与Charles E. Schmidt医学院、美国丹娜-法伯癌症研究所癌症生物学系等研究单位的联合研究团队，将他们的 一项突破性研究成果，以Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model为题在线发表在Science上。

该研究表明：通过诱导成人神经的发生（即诱导AHH的发生）与提升脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）的水平的结合操作来模拟运动训练，可以有效改善AD小鼠的认知能力【6】。

本研究中，研究者们旨在阐明如下两个科学问题：(i) 是否AHN能被强化？能否被作为一种治疗AD的途径？(ii) 是否AHN的损伤对AD的发病机制具有某种调控？

为了有力回答这两个问题。首先，研究者们通过对5×FAD小鼠（家族型AD小鼠模型）喂养注射P7C3（P7C3是NAMPT（烟酰胺磷酸核糖转移酶）的激活剂，能够提高大鼠的学习和记忆能力，能够保护新生神经元减轻细胞死亡）以及海马内微注射慢病毒表达的WNT3蛋白后，证实强化后的AHN是否能改善AD的病理和行为障碍。其次，揭示运动（运动是一种良好的神经源性刺激）的作用；且将强化后的AHN与由运动诱发的有益生物化学变化两者相结合，并观察能否改善小鼠的病理和行为障碍。最后，阐明在辐照、替莫唑胺（temozolomide）、显性抑制性WNT条件下，AHN的抑制否是会诱发AD、以及AHN在AD中的功能。

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.

最终研究者们发现：强化后的AHN能够改善AD的病理及认知缺陷。且强化后的AHN与过表达BDNF的联合操作，会有效模拟运动对认知缺陷的改善。相反地，抑制AHN会导致认知能力的恶化、以及对现存齿状神经元的缺失。因此，这种成人神经细胞发生和BDNF共操作可以有效改善AD患者的认知能力、减缓神经元死亡，可作为AD的一种强有力的潜在的疾病修饰治疗途径（如上图）。

补充阅读

通讯作者简介

Rudolph E. Tanzi, Ph.D.

Investigator
Neurology, Massachusetts General Hospital

Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation
Harvard Medical School

Research Staff
Neurology, Massachusetts General Hospital

Email: [e-mail]

Research Interests

alzheimer disease; amyloid beta-peptides; amyloid beta-protein precursor; amyloid precursor protein secretases; apolipoproteins e; caspases; genetic predisposition to disease; isoflurane; presenilin-1

Research Narrative

Dr. Rudolph Tanzi is the Vice-Chair of Neurology and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital, and serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. 

Dr. Tanzi received his B.S. (microbiology) and B.A. (history) at the University of Rochester in 1980 and his Ph.D. (neurobiology) at Harvard Medical School in 1990. In his research achievements, Dr. Tanzi served on the team that was the first to find a disease gene ((Huntington’s disease) using human genetic markers, helping to launch the field of neurogenetics. He later co-discovered all three early-onset familial Alzheimer’s disease genes and identified several others as leader of the Cure Alzheimer’s Fund Alzheimer’s Genome Project. He also co-discovered the Wilson’s disease gene and several other neurological disease genes. 

Most recently, he and his team used Alzheimer’s genes and human stem cells to create what the New York Times coined, “Alzheimer’s-in-a-Dish”. This is a three-dimensional human stem cell-derived neural culture system that is considered to be the first true model of Alzheimer’s disease, recapitulating both pathological hallmarks of Alzheimer’s disease: plaques and tangles. The model has made drug screening for Alzheimer’s disease 10 times cheaper and 10 times faster.

Dr. Tanzi has developed novel therapeutics for AD including gamma secretase modulators and metal chaperones (PBT; Prana) aimed at lowering plaque and tangle pathology. Both have been entered into clinical trials for Alzheimer’s patients. 

Dr. Tanzi is also very active in the areas of integrative medicine and applications to brain health. In this regard, along with Dr. Deepak Chopra, Dr. Tanzi co-directs the Self-Directed Biological Transformation Initiative (SBTI) aimed at exploring and quantifying the effects of lifestyle interventions on neuroplasticity and epigenetics.

Dr. Tanzi has published over 500 research papers and has received the highest awards in his field, including the Metropolitan Life Foundation Award, Potamkin Prize, Ronald Reagan Award, Silver Innovator Award, and many others. He was named to TIME magazine’s 2015 list of TIME100 Most Influential People in the World, and received the Smithsonian American Ingenuity Award, the top national award for invention and innovation. He co-authored the popular trade books “Decoding Darkness”, New York Times best seller, “Super Brain”, and international best seller  “Super Genes” with Dr. Deepak Chopra. He was named by GQ magazine as a Rock Star of Science, and in his spare time, has played keyboards with the band Aerosmith. With singer, Chris Mann, he also composed the beautiful ballad, “Remember Me”, which honors Alzheimer’s patients, and is being used to raise funds for Alzheimer’s research at the Cure Alzheimer’s Fund, for which, Dr. Tanzi serves as Chair of the Cure Alzheimer’s Fund Research Consortium.

参考文献

【1】R. E. Tanzi, L. Bertram, Twenty years of the Alzheimer’s disease amyloid hypothesis: A genetic perspective. Cell 120, 545–555 (2005).

【2】P. S. Eriksson et al., Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).

【3】Y. Mu, F. H. Gage, Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol. Neurodegener. 6, 85–93 (2011).

【4】D. Gomez-Nicola et al., Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration. Brain 137, 2312–2328 (2014).

【5】K. Jin et al., Increased hippocampal neurogenesis in Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 101, 343–347 (2004).

【6】M. A. Lovell, et al., Isolation of neural precursor cells from Alzheimer’s disease and aged control postmortem brain. Neurobiol. Aging 27, 909–917 (2006).

【7】Choi et al.,Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science  361, eaan8821 (2018)

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