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Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models

Nature Aging volume 1, pages 1162–1174 (2021)Cite this article

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Abstract

Amyloid-induced neurodegeneration plays a central role in Alzheimer’s disease (AD) pathogenesis. Here, we show that telomerase reverse transcriptase (TERT) haploinsufficiency decreases brain-derived neurotrophic factor and increases amyloid-β precursor in the murine brain. Moreover, before disease onset, the TERT locus sustains accumulation of repressive epigenetic marks in murine and human AD neurons, implicating TERT repression in amyloid-induced neurodegeneration. To test the impact of sustained TERT expression on AD pathobiology, AD mouse models were engineered to maintain physiological levels of TERT in adult neurons, resulting in reduced amyloid-β accumulation, improved spine morphology and preserved cognitive function. Mechanistically, integrated profiling revealed that TERT interacts with β-catenin and RNA polymerase II at gene promoters and upregulates the gene networks governing synaptic signaling and learning processes. These TERT-directed transcriptional activities do not require its catalytic activity nor telomerase RNA. These findings provide genetic proof of concept for somatic TERT gene activation therapy in attenuating AD progression including cognitive decline.

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Fig. 1: Tert insufficiency enhances APP and reduces mature BDNF levels in mouse brains.
Fig. 2: Downregulation of Tert via H3K9me3-dependent heterochromatin in two distinct AD mouse models.
Fig. 3: TERT activation not only alleviates amyloid pathology but enhances synaptic pathways and neural networks in an AD mouse model.
Fig. 4: TERT activation alleviates amyloid pathology in human iPSC-derived neurons and ameliorates learning and memory deficits in AD.
Fig. 5: TERT interacts with β-catenin-containing transactivation complex and is recruited to the promoters of specific target genes in AD neurons.

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Data availability

The RNA-seq data have been deposited in the Gene Expression Omnibus under accession nos. GSE163523, GSE163524 and GSE163525 and the ChIP–seq data in the Sequence Read Archive under accession nos. PRJNA633993 and PRJNA633994. The MS data have been deposited in MassIVE repository under accession no. MSV000088190. All other data are available from the corresponding author upon reasonable request.

References

  1. Huang, Y. D. & Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25years. EMBO Mol. Med. 8, 595–608 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Näslund, J. et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 283, 1571–1577 (2000).

  5. Tarasoff-Conway, J. M. et al. Clearance systems in the brain–implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Schindowski, K., Belarbi, K. & Buée, L. Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes Brain Behav. 7, 43–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miranda, M., Morici, J. F., Zanoni, M. B. & Bekinschtein, P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front. Cell Neurosci. 13, 363 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sampaio, T. B., Savall, A. S., Gutierrez, M. E. Z. & Pinton, S. Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: implications for pathogenesis and therapy. Neural Regen. Res. 12, 549–557 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nagahara, A. H. & Tuszynski, M. H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat. Rev. Drug Discov. 10, 209–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Chiodi, I. & Mondello, C. Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria. Front. Oncol. 2, 133 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Günes, C. & Rudolph, K. L. The role of telomeres in stem cells and cancer. Cell 152, 390–393 (2013).

    Article  PubMed  Google Scholar 

  13. Blasco, M. A. Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet. 6, 611–622 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Wong, K.-K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Yankner, B. A., Lu, T. & Loerch, P. The aging brain. Annu. Rev. Pathol. 3, 41–66 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Spilsbury, A., Miwa, S., Attems, J. & Saretzki, G. The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J. Neurosci. 35, 1659–1674 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eitan, E. et al. Excitotoxic and radiation stress increase TERT levels in the mitochondria and cytosol of cerebellar Purkinje neurons. Cerebellum 15, 509–517 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kang, H. J. et al. Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity. J. Neurosci. 24, 1280–1287 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. O’Brien, R. J. & Wong, P. C. Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci. 34, 185–204 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat. Genet. 36, 877–882 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Pang, P. T. et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Oddo, S. et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dixit, D., Ghildiyal, R., Anto, N. P. & Sen, E. Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. Cell Death Dis. 5, e1212 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chase, K. A. et al. Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models. PLoS ONE 14, e0216463 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu, J. et al. Chromatin landscape defined by repressive histone methylation during oligodendrocyte differentiation. J. Neurosci. 35, 352–365 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Yamagata, Y. et al. Kinase-dead knock-in mouse reveals an essential role of kinase activity of Ca2+/calmodulin-dependent protein kinase IIα in dendritic spine enlargement, long-term potentiation, and learning. J. Neurosci. 29, 7607–7618 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fakhoury, M. Microglia and astrocytes in Alzheimer’s disease: implications for therapy. Curr. Neuropharmacol. 16, 508–518 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lackie, R. E. et al. The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Front. Neurosci. 11, 254 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Rosenzweig, R., Nillegoda, N. B., Mayer, M. P. & Bukau, B. The Hsp70 chaperone network. Nat. Rev. Mol. Cell Biol. 20, 665–680 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Perera, O. N. et al. Telomerase promotes formation of a telomere protective complex in cancer cells. Sci. Adv. 5, eaav4409 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Palop, J. J. & Mucke, L. Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat. Neurosci. 13, 812–818 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Israel, M. A. et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Qin, W. et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281, 21745–21754 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Herskovits, A. Z. & Guarente, L. SIRT1 in neurodevelopment and brain senescence. Neuron 81, 471–483 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Evans, C. G., Wisén, S. & Gestwicki, J. E. Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro. J. Biol. Chem. 281, 33182–33191 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Vallée, A. & Lecarpentier, Y. Alzheimer disease: crosstalk between the canonical Wnt/Beta-catenin pathway and PPARs alpha and gamma. Front. Neurosci. 10, 459 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Park, J. I. et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460, 66–72 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhu, H., Fu, W. & Mattson, M. P. The catalytic subunit of telomerase protects neurons against amyloid β-peptide-induced apoptosis. J. Neurochem. 75, 117–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Dulac, C. Brain function and chromatin plasticity. Nature 465, 728–735 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bonasio, R., Tu, S. & Reinberg, D. Molecular signals of epigenetic states. Science 330, 612–616 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sidler, C., Kovalchuk, O. & Kovalchuk, I. Epigenetic regulation of cellular senescence and aging. Front. Genet. 8, 138 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Snigdha, S. et al. H3K9me3 inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus. J. Neurosci. 36, 3611–3622 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Christopher, M. A. et al. LSD1 protects against hippocampal and cortical neurodegeneration. Nat. Commun. 8, 805 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zhang, Z. et al. Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395, 698–702 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Kitazawa, M. et al. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer’s disease model. J. Immunol. 187, 6539–6549 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. De Ferrari, G. V. & Moon, R. T. The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene 25, 7545–7553 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Kim, K. C. et al. Overexpression of telomerase reverse transcriptase induces autism-like excitatory phenotypes in mice. Mol. Neurobiol. 53, 7312–7328 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Rao, S., Ye, N., Hu, H., Shen, Y. & Xu, Q. Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk. Am. J. Med. Genet. B Neuropsychiatr. Genet. 171B, 317–324 (2016).

    Article  PubMed  Google Scholar 

  54. Lee, J. et al. TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene 27, 3754–3760 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Miwa, S. et al. Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria. Aging (Albany) 8, 2551–2567 (2016).

    Article  CAS  Google Scholar 

  56. Tomás-Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008).

    Article  PubMed  Google Scholar 

  57. Eitan, E. et al. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol. Med. 4, 313–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Blackburn, E. H., Epel, E. S. & Lin, J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350, 1193–1198 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Chakravarti, D. et al. Telomere dysfunction activates YAP1 to drive tissue inflammation. Nat. Commun. 11, 4766 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Thai, T.-H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Kaech, S. & Banker, G. Culturing hippocampal neurons. Nat. Protoc. 1, 2406–2415 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Beaudoin, G. M. J. 3rd et al. Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat. Protoc. 7, 1741–1754 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Raja, W. K. et al. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS ONE 11, e0161969 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Brennand, K. J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hu, B.-Y. & Zhang, S.-C. Differentiation of spinal motor neurons from pluripotent human stem cells. Nat. Protoc. 4, 1295–1304 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Brewer, G. J. & Torricelli, J. R. Isolation and culture of adult neurons and neurospheres. Nat. Protoc. 2, 1490–1498 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Guo, W., Patzlaff, N. E., Jobe, E. M. & Zhao, X. Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. Nat. Protoc. 7, 2005–2012 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Terranova, C. et al. An integrated platform for genome-wide mapping of chromatin states using high-throughput ChIP–sequencing in tumor tissues. J. Vis. Exp. (134), 56972 (2018).

  73. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Li, H. et al. The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zhang, Y. et al. Model-based analysis of ChIP–Seq (MACS). Genome Biol. 9, R137 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zhong, F. L. et al. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150, 481–494 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Weinrich, S. L. et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat. Genet. 17, 498–502 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Shim, H. S., Wei, M., Brandhorst, S. & Longo, V. D. Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer Res. 75, 1056–1067 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Herbert, B.-S., Hochreiter, A. E., Wright, W. E. & Shay, J. W. Nonradioactive detection of telomerase activity using the telomeric repeat amplification protocol. Nat. Protoc. 1, 1583–1590 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Patil, S. S., Sunyer, B., Höger, H. & Lubec, G. Evaluation of spatial memory of C57BL/6J and CD1 mice in the Barnes maze, the Multiple T-maze and in the Morris water maze. Behav. Brain Res. 198, 58–68 (2009).

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all members of the Ronald A. DePinho laboratory for the discussion and constructive suggestions for this project; S. Artandi for providing the human TERT cDNA construct; L. Goldstein for providing the iPSC lines from the NDC and APPDp patient. This work was supported by the National Institutes of Health (no. R01 CA084628 and no. R01 CA231349), the Mathers Foundation (R.A.D) and a generous gift from Robert and Renee Belfer to the Neurodegeneration Consortium (R.A.D.). This study made use of the MD Anderson Cancer Center (MDACC) Advanced Technology Genomics Core (NCI CA016672), Research Histology, Pathology and Imaging Core (DHHS/NCI P30 CA16672) and MDACC Advanced Microscopy Core (NIH 1S10 RR029552) and the University of Texas Southwestern Proteomics Core.

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hong Seok Shim, Jiexi Li, Zheng D. Lan, Wen-Hao Hsu, Pingna Deng, Y. Alan Wang & Ronald A. DePinho

  2. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    James W. Horner, Shan Jiang, Xueping Xu & Ivonne I. Flores

  3. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Chang-Jiun Wu

  4. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Tomasz Zal

  5. Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    Yuan-Ta Lin & Li-Huei Tsai

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Contributions

H.S.S. and R.A.D. conceived the study. H.S.S. performed the experiments. J.W.H. generated the R26-CAG-LSL-mTert knock-in mouse. C.-J.W., J.L. and W.-H.H. analyzed the RNA-seq data. J.L. and Z.D.L. analyzed the ChIP–seq data. T.Z. assisted with the reflectance confocal imaging. Y.-T.L. and L.-H.T. provided the iPSC-derived human NPCs. S.J., X.X., I.I.F. and P.D. helped with mouse colony maintenance. H.S.S. and R.A.D. wrote the manuscript. H.S.S. and R.A.D. edited the manuscript with input from all coauthors. R.A.D. and Y.A.W. supervised the work and gave final approval for this study.

Corresponding authors

Correspondence to Y. Alan Wang or Ronald A. DePinho.

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Competing interests

The authors declare no competing interests specifically related to this work. R.A.D. is a founder, advisor and/or director of Tvardi Therapeutics, Nirogy Therapeutics, Stellanova Therapeutics, Sporos Bioventures and Asylia Therapeutics, which are focused on therapies for cancer, fibrosis and/or inflammation.

Additional information

Peer review information Nature Aging thanks Jing Zhao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Mouse primary cortical and hippocampal neuronal culture and gene expression profile of histone methyltransferases and demethylases in 5xFAD neurons.

a, Brightfield images of primary hippocampal and cortical neurons isolated from 5xFAD last-stage embryos (E18.5). b, Immunoblots for full-length APP and oligomeric amyloid-β in primary cortical and hippocampal neurons from 5xFAD and non-transgenic control mice at 1, 8, 14 and 21 DIV. A tubulin was used as a loading control. Experiments in a-b were repeated three times independently with similar results. c, d, mRNA expression levels of each histone methyltransferase (c) or demethylase (d) in cortical and hippocampal neurons isolated from 5xFAD and non-transgenic control mice at 2~3-month-old. Transcript levels were normalized to Hprt1 mRNA (n = 3 per group). e, Quantification of KDM1A staining intensity in the CA1 hippocampal subfield of 5xFAD and wildtype littermate control mice (n = 4 per group, p = 0.0003). Data are mean ± s.e.m. ***P < 0.001; ns, not significant (two-tailed unpaired t-test).

source data

Extended Data Fig. 2 Generation of Cre-inducible Tert knock-in mouse (R26-CAG-LSL-mTert).

a, Genotyping results of the original ES targeted lines carrying the R26-CAG-LSL-mTert-IRES-eGFP-pA alleles. b, Representative photographs of chimeric mice obtained from targeted ES cells. c, Aβ immunostaining in the hippocampus of adult (7-month-old) control and Tert-activated R26-CAG-LSL-mTert; 5xFAD; Camk2a-CreERT2 mice. Experiments were repeated three times independently with similar results. Scale bar, 300 μm.

Extended Data Fig. 3 The effects of TERT induction on neuroinflammation associated with activation of astrocytes and microglia.

a, Immunohistochemical staining for the astrocytic marker GFAP in the CA1 hippocampal subfield of adult control and Tert-activated R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mice. Scale bar, 100 μm. b, Quantitative comparison of GFAP-positive astrocytes in the hippocampus (n = 4 per group, 8-month-old, p = 0.0177). c, IBA-1 immunostaining in the CA1 hippocampal subfield of adult control and Tert-activated R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mice. Scale bar, 100 μm. d, Quantification of IBA1-positive activated microglia in the mouse hippocampus (n = 4 per group, p = 0.0015). Data are mean ± s.e.m. *P < 0.05, **P < 0.01 (two-tailed unpaired t-test).

source data

Extended Data Fig. 4 Significantly up- or down-regulated genes identified in RNA-Seq of Tert-activated R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mouse neurons.

a, mRNA levels of Tert and Terc in control and Tert-activated neurons isolated from R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mouse brains (n = 4 per group; p = 0.0391, p > 0.9999, respectively). b, mRNA levels of significantly downregulated genes in Tert-activated neurons compared to control (n = 4 per group; p = 0.0089, p = 0.0001, p = 0.0031, p = 0.0002, p = 0.0375, p = 0.0462, p = 0.0714, p = 0.0011, p = 0.0084, p = 0.0002, p = 0.0498, p = 0.0015, p = 0.002, p = 0.0438, respectively). c, mRNA levels of significantly upregulated genes in Tert-activated neurons compared to control (n = 4 per group; p = 0.0029, p = 0.0026, p = 0.0048, p = 0.0019, p = 0.0024, p = 0.0129, p = 0.0154, p = 0.0036, p = 0.0032, p = 0.0044, p = 0.0005, p = 0.0311, p = 0.01, p = 0.0063, p = 0.0063, p = 0.0225, p = 0.0005, p = 0.0403, p = 0.0129, respectively). d,e, Validation of App and ApoE mRNA (d) and protein (e) expression levels in the mouse brains of control (-TAM) and Tert-activated (+TAM) R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mice by quantitative RT-PCR (n = 4 per group; p = 0.0134, p = 0.0061, respectively) and immunoblotting. Data are mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant (two-tailed unpaired t-test).

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Extended Data Fig. 5 Tert expression in mouse adult neurons and neural stem cells as well as during neuronal maturation.

a, Mouse brain section showing the subventricular zone (SVZ) and cerebral cortex (Cx) for harvesting NSCs and neurons. Scale bar, 500 μm. b, mRNA levels of Tert gene in neural stem cells (NSCs) and neurons isolated from the brains of R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mouse with or without tamoxifen treatment (n = 7 (NSCs), 5 (neurons), 7 (neurons + TAM group); p < 0.0001, p = 0.0033, respectively). c, Tert mRNA levels during neuronal maturation of primary cortical and hippocampal neurons from 3xTg-AD mice at 1, 8, 14 and 21 DIV (n = 6 per group; day 1 vs. day 21: p < 0.0001). Data are mean ± s.e.m. **P < 0.01, ****P < 0.0001 (two-tailed unpaired t-test).

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Extended Data Fig. 6 Sixty-four (64) pathways activated in both mouse cortical and hippocampal neurons isolated from TERT-AD mice upon Tert activation.

Boxplots showing the Tert-induced fold changes of all the upregulated coding genes in Tert-activated cortical (Mouse_C) and hippocampal (Mouse_H) neurons isolated from R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mouse brains compared to each untreated and matched control group. For all box plots, each dot represents the average value of differentially expressed gene found in the comparison; centre lines denote medians; box limits denote 25th–75th percentile (Q1-Q3); whiskers are drawn up to the smallest or largest observed value that is still within 1.5 times the interquartile range below the first quartile or above the third quartile, respectively; all other observed points are plotted as outliers. p values were calculated by two-tailed Student’s t test.

Extended Data Fig. 7 TERT levels in NDC- and APPDp-derived neurons, cloning of wild-type and catalytically inactive Flag-hTERT lentiviral vector and quantification of immunoblots shown in Fig. 4.

a,b, TERT mRNA (a) and protein (b) levels in the neurons derived from NDC- and APPDp-derived iPSCs. c, Quantification of immunoblots in Fig. 4d. The values were normalized to respective control band intensity (n = 3; TERT: p = 0.0053, p = 0.0007, respectively, G9A: p < 0.0001, p < 0.0001, respectively, SETDB1: p < 0.0001, p < 0.0001, respectively). d, Schematic of wild-type Flag-tagged human TERT lentiviral expression construct. e, Immunoblots for the confirmation of 3xFlag-TERT expression in HEK293 cells. A tubulin was used as a loading control. Experiments were repeated three times independently with similar results. f, Quantification of immunoblots in Fig. 4g (n = 3 per group; APP: p = 0.0024, p < 0.0001, respectively, SIRT1: p = 0.0006, p = 0.0002, respectively, HSP70: p = 0.0228, p = 0.0037, respectively). Data are mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; ns, not significant (two-tailed unpaired t-test (a) or two-way ANOVA with Tukey’s multiple comparisons test (c,f)). g, Schematic of catalytically inactive (CI) human TERT lentiviral expression construct. The white asterisk indicates the position of the single mutation D712A, which renders the protein catalytically inactive. h, Immunoblots for the confirmation of Flag-tagged catalytically inactive TERT expression in HEK293 cells. A tubulin was used as a loading control. Experiments were repeated three times independently with similar results. i, mRNA expression levels of each gene indicated in EGFP-, wildtype (WT) TERT- or catalytically inactive (CI) TERT-transduced APPDp neurons (n = 4; EGFP vs. WT and EGFP vs. CI: TERT: p = 0.0003, p = 0.0003, respectively, SIRT1: p = 0.0031, p = 0.0014, respectively, BDNF: p = 0.0001, p < 0.0001, respectively, PSD95: p = 0.0081, p = 0.0021, respectively, HSF1: p = 0.0014, p = 0.0005, respectively, HSP70-1: p = 0.0041, p = 0.0006, respectively, NRF2: p = 0.0053, p = 0.0052, respectively, HO1: p = 0.0024, p = 0.0005, respectively). Transcript levels were normalized to HPRT1 mRNA. Data are mean ± s.e.m. **P < 0.01, ***P < 0.001, ****P < 0.0001; ns, not significant (two-way ANOVA with Tukey’s multiple comparisons test).

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Extended Data Fig. 8 Thirteen (13) pathways activated in mouse cortical and hippocampal AD neurons as well as in human iPSC-derived APPDp neurons upon TERT activation.

Violin plots showing the TERT-induced fold changes of all the upregulated coding genes in Tert-activated cortical neurons (Mouse_C) and hippocampal neurons (Mouse_H) isolated from R26-CAG-LSL-mTert; 3xTg-AD; Camk2a-CreERT2 mouse brains as well as TERT-activated human iPSC-derived APPDp neurons (Human) compared to each matched control group.

Extended Data Fig. 9 TERT contributes to β-Catenin/TCF-mediated transactivation in AD neurons.

At the early pathological stage of AD, Aβ oligomers induce the transcriptional repression of TERT gene via the propagation of heterochromatin in neurons. Genetic depletion and pharmacological inhibition of H3K9 methyltransferases (HMTs) can de-repress TERT gene suppression. TERT protein is able to interact with RNA pol II core transactivation machinery through β-Catenin and triggers the transcriptional induction of specific genes associated with neuronal survival and synaptic function in AD neurons, enabling to alleviate cognitive deficits.

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Unprocessed western blots for Extended Data Fig. 7.

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Shim, H.S., Horner, J.W., Wu, CJ. et al. Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models. Nat Aging 1, 1162–1174 (2021). https://doi.org/10.1038/s43587-021-00146-z

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