Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology.
Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology.
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DOI：
10.1073/pnas.1813205115
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发表时间：
2018-11-06
影响因子：
11.1
通讯作者：
Mira H
中科院分区：
文献类型：
--
作者：
Díaz-Moreno M;Armenteros T;Gradari S;Hortigüela R;García-Corzo L;Fontán-Lozano Á;Trejo JL;Mira H
阿尔茨海默病（AD）是与年龄相关的神经变性的最常见原因。损伤最初发生在海马体，海马体是大脑中形成记忆所必需的神经源性区域。由于阿尔茨海默病无法治愈，治疗策略可能有助于减缓海马功能障碍是必要的。我们描述了一个模拟病理性ad样神经变性发病的小鼠模型的早熟海马干细胞丢失。这种损失是由于BMP6的增加限制了神经发生。我们证明，通过给予Noggin阻断BMP信号传导有利于海马微环境，恢复干细胞数量、神经发生和行为。我们的研究结果支持进一步将BMP拮抗剂开发成可翻译的分子，用于拯救干细胞和神经变性/衰老中的神经发生。年龄增长是已知的散发性迟发性神经退行性疾病（如阿尔茨海默病（AD））的最大危险因素。阿尔茨海默病中受影响最严重的大脑区域之一是海马体，这是一个包含具有神经发生能力的成体神经干细胞（NSCs）的特殊结构。随着年龄的增长，海马神经发生减少，阿尔茨海默病加剧了这种减少，但这种进行性下降的机制原因在很大程度上仍未被探索。我们通过分析衰老加速小鼠易感8 （SAMP8）菌株来研究年龄对NSCs和神经发生的影响，SAMP8是一种非转基因的短寿菌株，自发发展出与AD相似的病理特征，并被用作研究从健康衰老到神经变性转变的模型系统。我们发现SAMP8小鼠表现出NSC库的加速丢失，这与BMP6蛋白的异常升高、典型BMP信号的增强和星形胶质细胞分化的增加相一致。体外实验表明，BMP6严重损害NSC的扩增并促进NSC向有丝分裂后星形胶质细胞分化。在SAMP8小鼠中，通过颅内递送拮抗剂Noggin阻断BMP通路的失调及其在体内的早成胶质作用，可恢复海马NSC数量、神经发生和行为。因此，调控NSC池的局部微环境可以抵消病理性衰老中的海马功能障碍。我们的研究结果揭示了一些干预措施，可以利用大脑的自然可塑性来增强成年后期和慢性神经退行性疾病（如阿尔茨海默病）的认知功能。
Alzheimer’s disease (AD) is the most common cause of age-related neurodegeneration. Damage initially occurs in the hippocampus, a neurogenic brain region essential in forming memories. Since there is no cure for AD, therapeutic strategies that may aid to slow hippocampal dysfunction are necessary. We describe the precocious hippocampal stem cell loss of a mouse model that mimics the onset of pathological AD-like neurodegeneration. The loss is due to an increase in BMP6 that limits neurogenesis. We demonstrate that blocking BMP signaling by means of Noggin administration is beneficial to the hippocampal microenvironment, restoring stem cell numbers, neurogenesis, and behavior. Our findings support further development of BMP antagonists into translatable molecules for the rescue of stem cells and neurogenesis in neurodegeneration/aging. Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer’s disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain’s natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.
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影响因子：
23.9
作者：
Encinas, Juan M.;Michurina, Tatyana V.;Peunova, Natalia;Park, June-Hee;Tordo, Julie;Peterson, Daniel A.;Fishell, Gord;Koulakov, Alex;Enikolopov, Grigori
通讯作者：
Enikolopov, Grigori
影响因子：
7.8
作者：
Drapeau E;Nora Abrous D
通讯作者：
Nora Abrous D
影响因子：
3.5
作者：
Li, Dabing;Tang, Jun;Yang, Li
通讯作者：
Yang, Li
成年V-SVZ神经干细胞壁ne衰老期间，祖细胞行为和基因表达的非单调变化。
影响因子：
5.9
作者：
Apostolopoulou M;Kiehl TR;Winter M;Cardenas De La Hoz E;Boles NC;Bjornsson CS;Zuloaga KL;Goderie SK;Wang Y;Cohen AR;Temple S
通讯作者：
Temple S
影响因子：
4.2
作者：
Meyers EA;Gobeske KT;Bond AM;Jarrett JC;Peng CY;Kessler JA
通讯作者：
Kessler JA