Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease.
Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease.
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新型药物治疗：NNI-362，一种变张力p70S6激酶刺激剂，在衰老和疾病模型中逆转认知和神经再生缺陷。
DOI：
10.1186/s13287-020-02126-3
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发表时间：
2021-01-13
影响因子：
7.5
通讯作者：
Kelleher-Andersson JA
中科院分区：
文献类型：
--
作者：
Sumien N;Wells MS;Sidhu A;Wong JM;Forster MJ;Zheng QX;Kelleher-Andersson JA
已知衰老会减缓海马体的神经原能力，海马体是哺乳动物仅有的两个成年神经原小生境之一。随着年龄的增长，成人出生的神经元的减少可能引发认知衰退进展，这在慢性神经退行性疾病中加剧，例如，阿尔茨海默病（AD）。随着生理性神经发生减少，但在衰老中仍然可行，这种神经元再生过程的非侵入性治疗调节仍然是可能的。真正新颖的神经元再生疗法的发现可以通过对促进来自人类神经祖细胞（hNPC）的成人出生的神经元的小分子的表型筛选来确定。通过鉴定神经元生成疗法和潜在的新作用机制，可以通过体内概念验证研究证实治疗益处。关键的衰老和长寿mTOR/p70 S6激酶轴是一种常见的靶向通路，是潜在的选择性激酶调节剂的底物，以促进来自NPC的新海马神经元。mTOR的高度调节的下游底物p70 S6激酶直接控制多效性细胞活性，包括翻译和细胞生长。刺激这种激酶，选择性地在一个成年神经原生态位，应促进NPC增殖，细胞生长和存活在海马。人类祖细胞神经发生的激酶谱和免疫细胞化学研究表明，新型小分子NNI-362刺激p70 S6激酶磷酸化，这反过来又促进NPC增殖和分化为神经元。NNI-362促进老年小鼠和唐氏综合征模型小鼠中年龄和疾病相关认知缺陷的联合逆转。这种口服的变构调节剂可能通过促进内源性海马再生，最终有益于涉及海马依赖性认知障碍的年龄相关神经退行性疾病，特别是AD。在线版本包含补充材料，可通过10.1186/s13287-020-02126-3获得。
Aging is known to slow the neurogenic capacity of the hippocampus, one of only two mammalian adult neurogenic niches. The reduction of adult-born neurons with age may initiate cognitive decline progression which is exacerbated in chronic neurodegenerative disorders, e.g., Alzheimer’s disease (AD). With physiologic neurogenesis diminished, but still viable in aging, non-invasive therapeutic modulation of this neuron regeneration process remains possible. The discovery of truly novel neuron regenerative therapies could be identified through phenotypic screening of small molecules that promote adult-born neurons from human neural progenitor cells (hNPCs). By identifying neuron-generating therapeutics and potentially novel mechanism of actions, therapeutic benefit could be confirmed through in vivo proof-of-concept studies. The key aging and longevity mTOR/p70S6 kinase axis, a commonly targeted pathway, is substrate for potential selective kinase modulators to promote new hippocampal neurons from NPCs. The highly regulated downstream substrate of mTOR, p70S6 kinase, directly controls pleiotropic cellular activities, including translation and cell growth. Stimulating this kinase, selectively in an adult neurogenic niche, should promote NPC proliferation, and cell growth and survival in the hippocampus. Studies of kinase profiling and immunocytochemistry of human progenitor neurogenesis suggest that the novel small molecule NNI-362 stimulates p70S6 kinase phosphorylation, which, in turn, promotes proliferation and differentiation of NPCs to neurons. NNI-362 promoted the associative reversal of age- and disease-related cognitive deficits in aged mice and Down syndrome-modeled mice. This oral, allosteric modulator may ultimately be beneficial for age-related neurodegenerative disorders involving hippocampal-dependent cognitive impairment, specifically AD, by promoting endogenous hippocampal regeneration. The online version contains supplementary material available at 10.1186/s13287-020-02126-3.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
5.3
作者：
Bianchi, Patrizia;Ciani, Elisabetta;Bartesaghi, Renata
通讯作者：
Bartesaghi, Renata
影响因子：
82.9
作者：
Eriksson, PS;Perfilieva, E;Gage, FH
通讯作者：
Gage, FH
影响因子：
56.9
作者：
Santarelli, L;Saxe, M;Hen, R
通讯作者：
Hen, R
成年人类海马神经发生的动力学。
影响因子：
64.5
作者：
Spalding KL;Bergmann O;Alkass K;Bernard S;Salehpour M;Huttner HB;Boström E;Westerlund I;Vial C;Buchholz BA;Possnert G;Mash DC;Druid H;Frisén J
通讯作者：
Frisén J