Laboratory of Chemical Biology and Division of Biological Inorganic Chemistry, State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences , Changchun, Jilin 130022, China.
J Am Chem Soc. 2015 Jan 28;137(3):1213-9. doi: 10.1021/ja511030s. Epub 2015 Jan 17.
It is well-known that aging is the most risk factor for Alzheimer's disease (AD). Recent studies have demonstrated that human telomerase is associated with pathological mechanisms of AD. In view of the central role of telomere and telomerase in the aging process, herein we found that the aggregated form Aβ (Aβ1-40 and Aβ1-42), not Aβ monomer, could inhibit telomerase activity both in vitro and in living cells. The β-sheet structures were essential for Aβ-induced telomerase inhibition. Further studies indicated Aβ oligomers inhibited telomerase activity through binding to DNA·RNA hybrid formed by telomeric DNA and the RNA template of telomerase, then blocking telomerase elongation of telomeric DNA. We also identified that intracellular Aβ localized at telomere, and induced cell senescence and telomere shortening. These results indicate that Aβ oligomers can be potential natural inhibitors of telomerase and that inhibition of telomerase activity may be one of the factors for Aβ-induced cytotoxicity. Our work may offer a new clue to a better understanding of aging and AD.
众所周知，衰老（aging）是阿尔茨海默病（Alzheimer's disease，AD）的最大风险因素。最近的研究表明，人类端粒酶（telomerase）与 AD 的病理机制有关。鉴于端粒和端粒酶在衰老过程中的核心作用，我们发现聚集态的 Aβ（Aβ1-40 和 Aβ1-42），而非 Aβ 单体，可在体外和活细胞中抑制端粒酶活性。β-折叠结构对于 Aβ 诱导的端粒酶抑制至关重要。进一步的研究表明，Aβ 寡聚体通过与端粒 DNA 和端粒酶 RNA 模板形成的 DNA·RNA 杂交体结合，抑制端粒酶对端粒 DNA 的延伸，从而抑制端粒酶活性。我们还发现细胞内 Aβ定位于端粒，诱导细胞衰老和端粒缩短。这些结果表明，Aβ 寡聚体可能是端粒酶的天然抑制剂，抑制端粒酶活性可能是 Aβ 诱导细胞毒性的因素之一。我们的工作可能为更好地理解衰老和 AD 提供新的线索。
