Sumien Nathalie, Wells Matthew S, Sidhu Akram, Wong Jessica M, Forster Michael J, Zheng Qiao-Xi, Kelleher-Andersson Judith A
Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, USA.
Neuronascent, Inc., 15601 Crabbs Branch Way, Rockville, MD, 20855, USA.
Stem Cell Res Ther. 2021 Jan 13;12(1):59. doi: 10.1186/s13287-020-02126-3.
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.
衰老会减缓海马体的神经发生能力，海马体是仅有的两个哺乳动物成年神经发生微环境之一。随着年龄增长，成年新生神经元数量减少可能引发认知衰退进程，而在慢性神经退行性疾病（如阿尔茨海默病，AD）中，这一进程会加剧。虽然生理性神经发生在衰老过程中会减少，但仍然存在，因此对这一神经元再生过程进行非侵入性治疗调节仍是可能的。通过对促进人类神经祖细胞（hNPCs）生成成年新生神经元的小分子进行表型筛选，有可能发现真正新颖的神经元再生疗法。通过确定能生成神经元的疗法及其潜在的新作用机制，可以通过体内概念验证研究来证实治疗效果。关键的衰老和长寿mTOR/p70S6激酶轴是一个常见的靶向通路，是潜在的选择性激酶调节剂促进NPCs生成新的海马神经元的作用底物。mTOR高度调控的下游底物p70S6激酶直接控制多种细胞活动，包括翻译和细胞生长。在成年神经发生微环境中选择性刺激这种激酶，应该能促进NPCs增殖以及海马体中的细胞生长和存活。对人类祖细胞神经发生的激酶谱分析和免疫细胞化学研究表明，新型小分子NNI-362能刺激p70S6激酶磷酸化，进而促进NPCs增殖并分化为神经元。NNI-362改善了老年小鼠和唐氏综合征模型小鼠与年龄和疾病相关的认知缺陷的联想反转。这种口服变构调节剂最终可能通过促进内源性海马体再生，对涉及海马体依赖性认知障碍的年龄相关性神经退行性疾病（特别是AD）有益。
