Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease
| العنوان: | 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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| المؤلفون: | Judith A. Kelleher-Andersson, Qiao-Xi Zheng, Michael J. Forster, Jessica M. Wong, Nathalie Sumien, Akram Sidhu, Matthew S. Wells |
| المصدر: | Stem Cell Research & Therapy Stem Cell Research & Therapy, Vol 12, Iss 1, Pp 1-6 (2021) |
| بيانات النشر: | BioMed Central, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Aging, Allosteric modulator, Neurogenesis, Short Report, Medicine (miscellaneous), Mice, Transgenic, Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), Hippocampus, Hippocampal neuron regeneration, lcsh:Biochemistry, Mice, Cognition, Alzheimer Disease, medicine, Animals, lcsh:QD415-436, Cognitive decline, PI3K/AKT/mTOR pathway, Human neural progenitors, lcsh:R5-920, BrdU+ neuron survival, Kinase, Regeneration (biology), Ribosomal Protein S6 Kinases, 70-kDa, Cell Biology, Neural stem cell, medicine.anatomical_structure, Molecular Medicine, mTOR/p70S6 kinase axis, Neuron, Stem cell, lcsh:Medicine (General), Neuroscience, Alzheimer’s disease |
| الوصف: | 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. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02126-3. |
| اللغة: | English |
| تدمد: | 1757-6512 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::30871a60e8acc17957ecd92456ee7b1f http://europepmc.org/articles/PMC7805132 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....30871a60e8acc17957ecd92456ee7b1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17576512 |
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