Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Friend or foe: role of pathological tau in neuronal death

Molecular Psychiatry (2023)Cite this article

Subjects

Abstract

Neuronal death is one of the most common pathological hallmarks of diverse neurological diseases, which manifest varying degrees of cognitive or motor dysfunction. Neuronal death can be classified into multiple forms with complicated and unique regulatory signaling pathways. Tau is a key microtubule-associated protein that is predominantly expressed in neurons to stabilize microtubules under physiological conditions. In contrast, pathological tau always detaches from microtubules and is implicated in a series of neurological disorders that are characterized by irreversible neuronal death, such as necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent neuronal death and phagocytosis by microglia. However, recent studies have also revealed that pathological tau can facilitate neuron escape from acute apoptosis, delay necroptosis through its action on granulovacuolar degeneration bodies (GVBs), and facilitate iron export from neurons to block ferroptosis. In this review, we briefly describe the current understanding of how pathological tau exerts dual effects on neuronal death by acting as a double-edged sword in different neurological diseases. We propose that elucidating the mechanism by which pathological tau affects neuronal death is critical for exploring novel and precise therapeutic strategies for neurological disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The dual roles of pathological tau in neuronal apoptosis.
Fig. 2: Pathological tau induces necroptosis on the one hand and may delay necroptosis through GVBs on the other hand.
Fig. 3: Pathological tau induces ferroptosis, and soluble tau exerts neuroprotective effects by reducing iron overload.
Fig. 4: Pathological tau induces pyroptosis.
Fig. 5: Pathological tau induces neuron phagocytosis by microglia.

References

  1. Bredesen DE, Rao RV, Mehlen P. Cell death in the nervous system. Nature. 2006;443:796–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal cell death. Physiol Rev. 2018;98:813–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet. 1994;344:769–72.

    Article  CAS  PubMed  Google Scholar 

  4. Schulz JB, Falkenburger BH. Neuronal pathology in Parkinson’s disease. Cell Tissue Res. 2004;318:135–47.

    Article  PubMed  Google Scholar 

  5. Guo Z, Rudow G, Pletnikova O, Codispoti KE, Orr BA, Crain BJ, et al. Striatal neuronal loss correlates with clinical motor impairment in Huntington’s disease. Mov Disord. 2012;27:1379–86.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Brettschneider J, Arai K, Del Tredici K, Toledo JB, Robinson JL, Lee EB, et al. TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol. 2014;128:423–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fung CW, Guo J, Fu H, Figueroa HY, Konofagou EE, Duff KE. Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy. Sci Adv. 2020;6:eabc8098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gorman AM. Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med. 2008;12:2263–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:49–60.

    Article  CAS  PubMed  Google Scholar 

  10. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125:777–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Di J, Cohen LS, Corbo CP, Phillips GR, El Idrissi A, Alonso AD. Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss. Sci Rep. 2016;6:20833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2020;21:21–35.

    Article  PubMed  Google Scholar 

  13. Li X, Yu H, Zhang B, Li L, Chen W, Yu Q, et al. Molecularly defined and functionally distinct cholinergic subnetworks. Neuron. 2022;110:3774–88.e3777.

    Article  CAS  PubMed  Google Scholar 

  14. Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci. 2005;25:10637–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;41:17–24.

    Article  PubMed  Google Scholar 

  16. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.

    Article  PubMed  Google Scholar 

  17. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA. 1988;85:4051–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–5.

    Article  CAS  PubMed  Google Scholar 

  19. Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017;133:665–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, et al. Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ. Acta Neuropathol. 1995;89:35–41.

    Article  CAS  PubMed  Google Scholar 

  21. Beard J. IV. On the early development of Lepidosteus osseus.—Preliminary notice. Proc R Soc Lond. 1890;46:108–18.

    Article  Google Scholar 

  22. Collin R. Histolyse de certains neuroblastes au cours du développement du tube nerveux chez le poulet. CR Soc Biol. 1906;60:1080–1.

    Google Scholar 

  23. Lockshin RA, Williams CM. Programmed cell death—II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J Insect Physiol. 1964;10:643–9.

    Article  CAS  Google Scholar 

  24. Kole AJ, Annis RP, Deshmukh M. Mature neurons: equipped for survival. Cell Death Dis. 2013;4:e689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Esteras N, Kundel F, Amodeo GF, Pavlov EV, Klenerman D, Abramov AY. Insoluble tau aggregates induce neuronal death through modification of membrane ion conductance, activation of voltage-gated calcium channels and NADPH oxidase. FEBS J. 2021;288:127–41.

    Article  CAS  PubMed  Google Scholar 

  26. Kimura T, Fukuda T, Sahara N, Yamashita S, Murayama M, Mizoroki T, et al. Aggregation of detergent-insoluble tau is involved in neuronal loss but not in synaptic loss. J Biol Chem. 2010;285:38692–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet. 1996;348:1339–42.

  28. Brown GC. Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons. Int J Mol Sci. 2021;22:13442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamaguchi Y, Miura M. Programmed cell death in neurodevelopment. Dev cell. 2015;32:478–90.

    Article  CAS  PubMed  Google Scholar 

  30. Arendt T, Brückner MK, Morawski M, Jäger C, Gertz HJ. Early neurone loss in Alzheimer’s disease: cortical or subcortical? Acta Neuropathol Commun. 2015;3:10.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bussière T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer’s disease: stereologic analysis of prefrontal cortex area 9. J Comp Neurol. 2003;463:281–302.

    Article  PubMed  Google Scholar 

  32. Martínez-Pinilla E, Ordóñez C, Del Valle E, Navarro A, Tolivia J. Regional and gender study of neuronal density in brain during aging and in Alzheimer’s disease. Front aging Neurosci. 2016;8:213.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Seward ME, Swanson E, Norambuena A, Reimann A, Cochran JN, Li R, et al. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer’s disease. J Cell Sci. 2013;126:1278–86. Pt 5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Drubin DG, Kirschner MW. Tau protein function in living cells. J Cell Biol. 1986;103:2739–46. 6 Pt 2.

    Article  CAS  PubMed  Google Scholar 

  35. Dabir DV, Robinson MB, Swanson E, Zhang B, Trojanowski JQ, Lee VM, et al. Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J Neurosci. 2006;26:644–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Seiberlich V, Bauer NG, Schwarz L, Ffrench-Constant C, Goldbaum O, Richter-Landsberg C. Downregulation of the microtubule associated protein tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes. Glia. 2015;63:1621–35.

    Article  PubMed  Google Scholar 

  37. Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013;14:389–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014;211:387–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron. 2011;70:410–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–26.

    Article  CAS  PubMed  Google Scholar 

  41. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 1989;8:393–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu C, Götz J. Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PloS One. 2013;8:e84849.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Alquezar C, Arya S, Kao AW. Tau post-translational modifications: dynamic transformers of Tau function, degradation, and aggregation. Front Neurol. 2020;11:595532.

    Article  PubMed  Google Scholar 

  44. Wesseling H, Mair W, Kumar M, Schlaffner CN, Tang S, Beerepoot P, et al. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease. Cell. 2020;183:1699–713.e1613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shin S, Kim D, Song JY, Jeong H, Hyeon SJ, Kowall NW, et al. Visualization of soluble tau oligomers in TauP301L-BiFC transgenic mice demonstrates the progression of tauopathy. Progr Neurobiol. 2020;187:101782.

    Article  CAS  Google Scholar 

  46. Noble W, Hanger DP, Miller CC, Lovestone S. The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol. 2013;4:83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA. 1994;91:5562–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010;68:1067–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Decker JM, Krüger L, Sydow A, Zhao S, Frotscher M, Mandelkow E, et al. Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation. Acta Neuropathol Commun. 2015;3:23.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Pooler AM, Noble W, Hanger DP. A role for tau at the synapse in Alzheimer’s disease pathogenesis. Neuropharmacology. 2014;76:1–8. Pt A.

    Article  CAS  PubMed  Google Scholar 

  51. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell. 2010;142:387–97.

    Article  CAS  PubMed  Google Scholar 

  52. Wu M, Zhang M, Yin X, Chen K, Hu Z, Zhou Q, et al. The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases. Transl Neurodegener. 2021;10:45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pampuscenko K, Morkuniene R, Krasauskas L, Smirnovas V, Tomita T, Borutaite V. Distinct neurotoxic effects of extracellular Tau species in primary neuronal-glial cultures. Mol Neurobiol. 2021;58:658–67.

    Article  CAS  PubMed  Google Scholar 

  54. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005;25:5446–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, Canu N. NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci USA. 2006;103:2892–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bano D, Ankarcrona M. Beyond the critical point: an overview of excitotoxicity, calcium overload and the downstream consequences. Neurosci Lett. 2018;663:79–85.

    Article  CAS  PubMed  Google Scholar 

  57. Ittner A, Chua SW, Bertz J, Volkerling A, van der Hoven J, Gladbach A, et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice. Science. 2016;354:904–8.

    Article  CAS  PubMed  Google Scholar 

  58. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;407:802–9.

    Article  CAS  PubMed  Google Scholar 

  60. Dickson DW. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J Clin Investig. 2004;114:23–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Green DR. Apoptotic pathways: paper wraps stone blunts scissors. Cell. 2000;102:1–4.

    Article  CAS  PubMed  Google Scholar 

  62. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Su JH, Zhao M, Anderson AJ, Srinivasan A, Cotman CW. Activated caspase-3 expression in Alzheimer’s and aged control brain: correlation with Alzheimer pathology. Brain Res. 2001;898:350–7.

    Article  CAS  PubMed  Google Scholar 

  64. Rohn TT, Head E, Su JH, Anderson AJ, Bahr BA, Cotman CW, et al. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am J Pathol. 2001;158:189–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ramalho RM, Viana RJ, Castro RE, Steer CJ, Low WC, Rodrigues CM. Apoptosis in transgenic mice expressing the P301L mutated form of human tau. Mol Med. 2008;14:309–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Britti E, Ros J, Esteras N, Abramov AY. Tau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calcium-induced cell death. Cell Calcium. 2020;86:102150.

    Article  CAS  PubMed  Google Scholar 

  67. Zhao Z, Ho L, Suh J, Qin W, Pyo H, Pompl P, et al. A role of P301L tau mutant in anti-apoptotic gene expression, cell cycle and apoptosis. Mol Cell Neurosci. 2003;24:367–79.

    Article  CAS  PubMed  Google Scholar 

  68. Justin Thenmozhi A, Dhivyabharathi M, Manivasagam T, Essa MM. Tannoid principles of Emblica officinalis attenuated aluminum chloride induced apoptosis by suppressing oxidative stress and tau pathology via Akt/GSK-3βsignaling pathway. J Ethnopharmacol. 2016;194:20–29.

    Article  CAS  PubMed  Google Scholar 

  69. Ahmad Rather M, Justin-Thenmozhi A, Manivasagam T, Saravanababu C, Guillemin GJ, Essa MM. Asiatic acid attenuated aluminum chloride-induced Tau pathology, oxidative stress and apoptosis via AKT/GSK-3β signaling pathway in Wistar rats. Neurotox Res. 2019;35:955–68.

    Article  CAS  PubMed  Google Scholar 

  70. Kang Q, Xiang Y, Li D, Liang J, Zhang X, Zhou F, et al. MiR-124-3p attenuates hyperphosphorylation of Tau protein-induced apoptosis via caveolin-1-PI3K/Akt/GSK3β pathway in N2a/APP695swe cells. Oncotarget. 2017;8:24314–26.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Zhang SG, Wang XS, Zhang YD, Di Q, Shi JP, Qian M, et al. Indirubin-3’-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation. Neural Regen Res. 2016;11:988–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Martin L, Page G, Terro F. Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A preferentially involve GSK3β. Neurochem Int. 2011;59:235–50.

    Article  CAS  PubMed  Google Scholar 

  73. Tao Q, Wang X, Liu L, Ji Y, Luo Q, Du J, et al. Toxoplasma gondii Chinese I genotype Wh6 strain infection induces tau phosphorylation via activating GSK3β and causes hippocampal neuron apoptosis. Acta Tropica. 2020;210:105560.

    Article  CAS  PubMed  Google Scholar 

  74. Xiao S, Wu Q, Yao X, Zhang J, Zhong W, Zhao J, et al. Inhibitory effects of isobavachalcone on Tau protein aggregation, Tau phosphorylation, and oligomeric Tau-induced apoptosis. ACS Chem Neurosci. 2021;12:123–32.

    Article  CAS  PubMed  Google Scholar 

  75. Xiao N, Zhang F, Zhu B, Liu C, Lin Z, Wang H, et al. CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic reticulum-associated degradation pathway. Toxicol Lett. 2018;292:97–107.

    Article  CAS  PubMed  Google Scholar 

  76. Nie CL, Wang XS, Liu Y, Perrett S, He RQ. Amyloid-like aggregates of neuronal Tau induced by formaldehyde promote apoptosis of neuronal cells. BMC Neurosci. 2007;8:9.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Sola M, Magrin C, Pedrioli G, Pinton S, Salvadè A, Papin S, et al. Tau affects P53 function and cell fate during the DNA damage response. Commun Biol. 2020;3:245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu M, Sui D, Dexheimer T, Hovde S, Deng X, Wang KW, et al. Hyperphosphorylation renders Tau prone to aggregate and to cause cell death. Mol Neurobiol. 2020;57:4704–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lin CI, Chang YC, Kao NJ, Lee WJ, Cross TW, Lin SH. 1,25(OH)(2)D(3) alleviates Aβ(25-35)-induced Tau hyperphosphorylation, excessive reactive oxygen species, and apoptosis through interplay with glial cell line-derived neurotrophic factor signaling in SH-SY5Y cells. Int J Mol Sci. 2020;21:4215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sun W, Samimi H, Gamez M, Zare H, Frost B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci. 2018;21:1038–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA, De Jager PL, et al. Tau activates transposable elements in Alzheimer’s Disease. Cell Rep. 2018;23:2874–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang HH, Li HL, Liu R, Zhang Y, Liao K, Wang Q, et al. Tau overexpression inhibits cell apoptosis with the mechanisms involving multiple viability-related factors. J Alzheimers Dis JAD. 2010;21:167–79.

    Article  CAS  PubMed  Google Scholar 

  83. Wang ZF, Yin J, Zhang Y, Zhu LQ, Tian Q, Wang XC, et al. Overexpression of tau proteins antagonizes amyloid-beta-potentiated apoptosis through mitochondria-caspase-3 pathway in N2a cells. J Alzheimers Dis JAD. 2010;20:145–57.

    Article  PubMed  Google Scholar 

  84. Liu XA, Song J, Jiang Q, Wang Q, Tian Q, Wang JZ. Expression of the hyperphosphorylated tau attenuates ER stress-induced apoptosis with upregulation of unfolded protein response. Apoptosis Int J Program Cell Death. 2012;17:1039–49.

    Article  CAS  Google Scholar 

  85. He A, Zhang C, Ke X, Yi Y, Yu Q, Zhang T, et al. VGLUT3 neurons in median raphe control the efficacy of spatial memory retrieval via ETV4 regulation of VGLUT3 transcription. Sci China Life Sci. 2022;65:1590–607.

    Article  CAS  PubMed  Google Scholar 

  86. Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci Off J Soc Neurosci. 2002;22:9340–51.

    Article  CAS  Google Scholar 

  87. Li HL, Wang HH, Liu SJ, Deng YQ, Zhang YJ, Tian Q, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer’s neurodegeneration. Proc Natl Acad Sci USA. 2007;104:3591–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu E, Zhou Q, Xie AJ, Li X, Li M, Ye J, et al. Tau acetylates and stabilizes β-catenin thereby promoting cell survival. EMBO Rep. 2020;21:e48328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu XA, Liao K, Liu R, Wang HH, Zhang Y, Zhang Q, et al. Tau dephosphorylation potentiates apoptosis by mechanisms involving a failed dephosphorylation/activation of Bcl-2. J Alzheimer’s Dis JAD. 2010;19:953–62.

    Article  CAS  PubMed  Google Scholar 

  90. Luo DJ, Feng Q, Wang ZH, Sun DS, Wang Q, Wang JZ, et al. Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation. J Neurochem. 2014;130:816–25.

    Article  CAS  PubMed  Google Scholar 

  91. de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, et al. Caspase activation precedes and leads to tangles. Nature. 2010;464:1201–4.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112–9.

    Article  CAS  PubMed  Google Scholar 

  93. Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 2017;24:1184–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tummers B, Green DR. Caspase-8: regulating life and death. Immunol Rev. 2017;277:76–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang J, Liu D, Fu P, Liu ZQ, Lai C, Yang CQ, et al. Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala. Mol Psychiatry. 2022;27:4050–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhu S, Zhang Y, Bai G, Li H. Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease. Cell Death Dis. 2011;2:e115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron. 2014;81:1001–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016;353:603–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang SH, Lee DK, Shin J, Lee S, Baek S, Kim J, et al. Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO Mol Med. 2017;9:61–77.

    Article  CAS  PubMed  Google Scholar 

  101. Jayaraman A, Htike TT, James R, Picon C, Reynolds R. TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus. Acta Neuropathol Commun. 2021;9:159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wu JR, Wang J, Zhou SK, Yang L, Yin JL, Cao JP, et al. Necrostatin-1 protection of dopaminergic neurons. Neural Regen Res. 2015;10:1120–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, et al. Necroptosis activation in Alzheimer’s disease. Nat Neurosci. 2017;20:1236–46.

    Article  CAS  PubMed  Google Scholar 

  104. Dong Y, Yu H, Li X, Bian K, Zheng Y, Dai M, et al. Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease. J Neuroinflammation. 2022;19:205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Koper MJ, Van Schoor E, Ospitalieri S, Vandenberghe R, Vandenbulcke M, von Arnim CAF, et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease. Acta Neuropathol. 2020;139:463–84.

    Article  CAS  PubMed  Google Scholar 

  106. Wiersma VI, van Ziel AM, Vazquez-Sanchez S, Nölle A, Berenjeno-Correa E, Bonaterra-Pastra A, et al. Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology. Acta Neuropathol. 2019;138:943–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bondareff W, Wischik CM, Novak M, Roth M. Sequestration of tau by granulovacuolar degeneration in Alzheimer’s disease. Am J Pathol. 1991;139:641–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Puladi B, Dinekov M, Arzberger T, Taubert M, Köhler C. The relation between tau pathology and granulovacuolar degeneration of neurons. Neurobiol Dis. 2021;147:105138.

    Article  CAS  PubMed  Google Scholar 

  109. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dixon SJ. Ferroptosis: bug or feature? Immunol Rev. 2017;277:150–7.

    Article  CAS  PubMed  Google Scholar 

  111. Sripetchwandee J, Pipatpiboon N, Chattipakorn N, Chattipakorn S. Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity. PloS One. 2014;9:e85115.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012;18:291–5.

    Article  CAS  PubMed  Google Scholar 

  113. Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA. 1997;94:9866–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, et al. Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology. 2007;68:1820–5.

    Article  CAS  PubMed  Google Scholar 

  115. Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F, et al. Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem. 2002;82:1137–47.

    Article  CAS  PubMed  Google Scholar 

  116. Xie L, Zheng W, Xin N, Xie JW, Wang T, Wang ZY. Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake. Neurochem Int. 2012;61:334–40.

    Article  CAS  PubMed  Google Scholar 

  117. Guo C, Wang P, Zhong ML, Wang T, Huang XS, Li JY, et al. Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int. 2013;62:165–72.

    Article  CAS  PubMed  Google Scholar 

  118. Wan W, Cao L, Kalionis B, Murthi P, Xia S, Guan Y. Iron deposition leads to hyperphosphorylation of Tau and disruption of insulin signaling. Front Neurol. 2019;10:607.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Zhang YH, Wang DW, Xu SF, Zhang S, Fan YG, Yang YY, et al. α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol. 2018;14:535–48.

    Article  CAS  PubMed  Google Scholar 

  120. Bao WD, Pang P, Zhou XT, Hu F, Xiong W, Chen K, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ. 2021;28:1548–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bao WD, Zhou XT, Zhou LT, Wang F, Yin X, Lu Y, et al. Targeting miR-124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model. Aging Cell. 2020;19:e13235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang S, Jiang Y, Liu Y, Liu Q, Sun H, Mei M, et al. Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3β activation and proteasome inhibition. Mol Neurobiol. 2022;59:1486–501.

    Article  CAS  PubMed  Google Scholar 

  123. Chen K, Jiang X, Wu M, Cao X, Bao W, Zhu LQ. Ferroptosis, a potential therapeutic target in Alzheimer’s disease. Front Cell Dev Biol. 2021;9:704298.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Lei P, Ayton S, Appukuttan AT, Moon S, Duce JA, Volitakis I, et al. Lithium suppression of tau induces brain iron accumulation and neurodegeneration. Mol Psychiatry. 2017;22:396–406.

    Article  CAS  PubMed  Google Scholar 

  125. Li X, Lei P, Tuo Q, Ayton S, Li QX, Moon S, et al. Enduring elevations of hippocampal amyloid precursor protein and iron are features of β-amyloid toxicity and are mediated by Tau. NeuroTherapeutics J Am Soc Exp NeuroTherapeutics. 2015;12:862–73.

    Article  CAS  Google Scholar 

  126. Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Li XL, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017;22:1520–30.

    Article  CAS  PubMed  Google Scholar 

  127. Lei P, Ayton S, Appukuttan AT, Volitakis I, Adlard PA, Finkelstein DI, et al. Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse. Neurobiol Dis. 2015;81:168–75.

    Article  CAS  PubMed  Google Scholar 

  128. Berger GE, Wood SJ, Ross M, Hamer CA, Wellard RM, Pell G, et al. Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. a longitudinal MRI/MRS study. Curr Pharm Des. 2012;18:570–5.

    Article  CAS  PubMed  Google Scholar 

  129. Rametti A, Esclaire F, Yardin C, Cogné N, Terro F. Lithium down-regulates tau in cultured cortical neurons: a possible mechanism of neuroprotection. Neurosci Lett. 2008;434:93–98.

    Article  CAS  PubMed  Google Scholar 

  130. Bi M, Gladbach A, van Eersel J, Ittner A, Przybyla M, van Hummel A, et al. Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun. 2017;8:473.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Chen W, Jiang L, Hu Y, Tang N, Liang N, Li XF, et al. Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal death through p53/SLC7A11-mediated ferroptosis. Brain Res. 2021;1752:147216.

    Article  CAS  PubMed  Google Scholar 

  132. Pei L, Wang S, Jin H, Bi L, Wei N, Yan H, et al. A novel mechanism of spine damages in stroke via DAPK1 and Tau. Cereb Cortex. 2015;25:4559–71.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Chen YD, Huang PY, Chiang CS, Huang YS, Tang SC. Generation and role of calpain-cleaved 17-kDa Tau fragment in acute ischemic stroke. Mol Neurobiol. 2021;58:5814–25.

    Article  CAS  PubMed  Google Scholar 

  134. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.

    Article  CAS  PubMed  Google Scholar 

  135. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111–6.

    Article  CAS  PubMed  Google Scholar 

  136. Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med. 2019;11:e10248.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575:669–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Shen H, Han C, Yang Y, Guo L, Sheng Y, Wang J, et al. Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer’s disease. Brain Behav. 2021;11:e02063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Li Y, Xu P, Shan J, Sun W, Ji X, Chi T, et al. Interaction between hyperphosphorylated tau and pyroptosis in forskolin and streptozotocin induced AD models. Biomed Pharmacother. 2020;121:109618.

    Article  CAS  PubMed  Google Scholar 

  140. Sui G, Yang C, Wang L, Xiong X, Guo M, Chen Z, et al. Exogenous IGF-1 improves tau pathology and neuronal pyroptosis in high-fat diet mice with cognitive dysfunction. Metab Brain Dis. 2021;36:2079–88.

    Article  CAS  PubMed  Google Scholar 

  141. Stancu IC, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018;19:610–21.

    Article  CAS  PubMed  Google Scholar 

  143. Tian D, Xing Y, Gao W, Zhang H, Song Y, Tian Y, et al. Sevoflurane aggravates the progress of Alzheimer’s disease through NLRP3/Caspase-1/Gasdermin D pathway. Front Cell Dev Biol. 2021;9:801422.

    Article  PubMed  Google Scholar 

  144. Panda C, Voelz C, Habib P, Mevissen C, Pufe T, Beyer C, et al. Aggregated Tau-PHF6 (VQIVYK) potentiates NLRP3 inflammasome expression and autophagy in human microglial cells. Cells. 2021;10:1652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Cai Y, Chai Y, Fu Y, Wang Y, Zhang Y, Zhang X, et al. Salidroside ameliorates Alzheimer’s disease by targeting NLRP3 inflammasome-mediated pyroptosis. Front Aging Neurosci. 2021;13:809433.

    Article  CAS  PubMed  Google Scholar 

  146. Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22:367–76.

    Article  CAS  PubMed  Google Scholar 

  147. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107–20.

    Article  CAS  PubMed  Google Scholar 

  148. Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 2008;9:1004–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Uchiyama Y, Koike M, Shibata M. Autophagic neuron death in neonatal brain ischemia/hypoxia. Autophagy. 2008;4:404–8.

    Article  CAS  PubMed  Google Scholar 

  150. Shi R, Weng J, Zhao L, Li XM, Gao TM, Kong J. Excessive autophagy contributes to neuron death in cerebral ischemia. CNS Neurosci Therapeutics. 2012;18:250–60.

    Article  CAS  Google Scholar 

  151. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147:728–41.

    Article  CAS  PubMed  Google Scholar 

  152. Berry DL, Baehrecke EH. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell. 2007;131:1137–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Denton D, Shravage B, Simin R, Mills K, Berry DL, Baehrecke EH, et al. Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Curr Biol. 2009;19:1741–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Nixon RA, Yang DS. Autophagy and neuronal cell death in neurological disorders. Cold Spring Harb Perspect Biol. 2012;4:a008839.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Shimizu S, Konishi A, Nishida Y, Mizuta T, Nishina H, Yamamoto A, et al. Involvement of JNK in the regulation of autophagic cell death. Oncogene. 2010;29:2070–82.

    Article  CAS  PubMed  Google Scholar 

  156. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004;6:1221–8.

    Article  CAS  PubMed  Google Scholar 

  157. Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, et al. Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA. 2006;103:4952–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lamy L, Ngo VN, Emre NC, Shaffer AL 3rd, Yang Y, Tian E, et al. Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell. 2013;23:435–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Qiu L, Ng G, Tan EK, Liao P, Kandiah N, Zeng L. Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice. Sci Rep. 2016;6:23964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Xu Y, Propson NE, Du S, Xiong W, Zheng H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc Natl Acad Sci USA. 2021;118:e2023418118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ji C, Tang M, Zeidler C, Höhfeld J, Johnson GV. BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes. Autophagy. 2019;15:1199–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun. 2014;5:3496.

    Article  PubMed  Google Scholar 

  163. Chambraud B, Daguinot C, Guillemeau K, Genet M, Dounane O, Meduri G, et al. Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during MAPT/Tau-induced proteotoxic stress. Autophagy. 2021;17:3491–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Meduri G, Guillemeau K, Dounane O, Sazdovitch V, Duyckaerts C, Chambraud B, et al. Caspase-cleaved Tau-D(421) is colocalized with the immunophilin FKBP52 in the autophagy-endolysosomal system of Alzheimer’s disease neurons. Neurobiol Aging. 2016;46:124–37.

    Article  CAS  PubMed  Google Scholar 

  165. Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O’Leary JC 3rd, Fontaine SN, et al. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Investig. 2013;123:4158–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Gassen NC, Hartmann J, Zannas AS, Kretzschmar A, Zschocke J, Maccarrone G, et al. FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications. Mol Psychiatry. 2016;21:277–89.

    Article  CAS  PubMed  Google Scholar 

  167. Caballero B, Bourdenx M, Luengo E, Diaz A, Sohn PD, Chen X, et al. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nat Commun. 2021;12:2238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L. Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PloS One. 2009;4:e5515.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Dai B, Zhong T, Chen ZX, Chen W, Zhang N, Liu XL, et al. Myricetin slows liquid-liquid phase separation of Tau and activates ATG5-dependent autophagy to suppress Tau toxicity. J Biol Chem. 2021;297:101222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Yang Z, Zhou C, Shi H, Zhang N, Tang B, Ji N. Heme induces BECN1/ATG5-mediated autophagic cell death via ER stress in neurons. Neurotox Res. 2020;38:1037–48.

    Article  CAS  PubMed  Google Scholar 

  171. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304:1500–2.

    Article  CAS  PubMed  Google Scholar 

  172. Choi GE, Lee HJ, Chae CW, Cho JH, Jung YH, Kim JS, et al. BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects. Nat Commun. 2021;12:487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Martinelli S, Anderzhanova EA, Bajaj T, Wiechmann S, Dethloff F, Weckmann K, et al. Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion. Nat Commun. 2021;12:4643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Silva JM, Rodrigues S, Sampaio-Marques B, Gomes P, Neves-Carvalho A, Dioli C, et al. Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death Differ. 2019;26:1411–27.

    Article  CAS  PubMed  Google Scholar 

  175. Feng Q, Luo Y, Zhang XN, Yang XF, Hong XY, Sun DS, et al. MAPT/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: a vicious cycle in Alzheimer neurodegeneration. Autophagy. 2020;16:641–58.

    Article  CAS  PubMed  Google Scholar 

  176. Bowles KR, Silva MC, Whitney K, Bertucci T, Berlind JE, Lai JD, et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell. 2021;184:4547–63.e4517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Zhang J, Cai T, Zhao F, Yao T, Chen Y, Liu X, et al. The role of α-synuclein and tau hyperphosphorylation-mediated autophagy and apoptosis in lead-induced learning and memory injury. Int J Biol Sci. 2012;8:935–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mann CN, Devi SS, Kersting CT, Bleem AV, Karch CM, Holtzman DM, et al. Astrocytic α2-Na(+)/K(+) ATPase inhibition suppresses astrocyte reactivity and reduces neurodegeneration in a tauopathy mouse model. Sci Transl Med. 2022;14:eabm4107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kurematsu C, Sawada M, Ohmuraya M, Tanaka M, Kuboyama K, Ogino T, et al. Synaptic pruning of murine adult-born neurons by microglia depends on phosphatidylserine. J Exp Med. 2022;219:e20202304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 2005;123:321–34.

    Article  CAS  PubMed  Google Scholar 

  181. Scott-Hewitt N, Perrucci F, Morini R, Erreni M, Mahoney M, Witkowska A, et al. Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J. 2020;39:e105380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Butler CA, Popescu AS, Kitchener EJA, Allendorf DH, Puigdellívol M, Brown GC. Microglial phagocytosis of neurons in neurodegeneration, and its regulation. J Neurochem. 2021;158:621–39.

    Article  CAS  PubMed  Google Scholar 

  183. Païdassi H, Tacnet-Delorme P, Garlatti V, Darnault C, Ghebrehiwet B, Gaboriaud C, et al. C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J Immunol. 2008;180:2329–38.

    Article  PubMed  Google Scholar 

  184. Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci. 2014;15:209–16.

    Article  CAS  PubMed  Google Scholar 

  185. Podleśny-Drabiniok A, Marcora E, Goate AM. Microglial phagocytosis: a disease-associated process emerging from Alzheimer’s disease genetics. Trends Neurosci. 2020;43:965–79.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG. Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol. 2004;165:1643–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Brelstaff J, Tolkovsky AM, Ghetti B, Goedert M, Spillantini MG. Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep. 2018;24:1939–48.e1934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Benetatos J, Bennett RE, Evans HT, Ellis SA, Hyman BT, Bodea LG, et al. PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy. Acta Neuropathol. 2020;140:7–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Brelstaff JH, Mason M, Katsinelos T, McEwan WA, Ghetti B, Tolkovsky AM, et al. Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates. Sci Adv. 2021;7:eabg4980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Hopp SC, Lin Y, Oakley D, Roe AD, DeVos SL, Hanlon D, et al. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J Neuroinflammation. 2018;15:269.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Pampuscenko K, Morkuniene R, Sneideris T, Smirnovas V, Budvytyte R, Valincius G, et al. Extracellular tau induces microglial phagocytosis of living neurons in cell cultures. J Neurochem. 2020;154:316–29.

    Article  CAS  PubMed  Google Scholar 

  192. Das R, Balmik AA, Chinnathambi S. Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia. J Neuroinflammation. 2020;17:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 2019;28:2111–23.e2116.

    Article  CAS  PubMed  Google Scholar 

  194. Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, et al. Complement C3aR inactivation attenuates Tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer’s disease. Neuron. 2018;100:1337–53.e1335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T, Srinivasan K, et al. Changes in the synaptic proteome in tauopathy and rescue of Tau-induced synapse loss by C1q antibodies. Neuron. 2018;100:1322–36.e1327.

    Article  CAS  PubMed  Google Scholar 

  196. Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015;5:11161.

    Article  PubMed  PubMed Central  Google Scholar 

  197. Desale SE, Chinnathambi S. α- Linolenic acid modulates phagocytosis and endosomal pathways of extracellular Tau in microglia. Cell Adhes Migr. 2021;15:84–100.

    Article  CAS  Google Scholar 

Download references

Funding

This study was partially supported by the National Key Research and Development Program of China (2019YFE0121200 to LQZ), the National Natural Science Foundation of China (82030032 to LQZ, 82261138555, 32070960 to DL, 82260209 and 81960221 to XPY, and 82260454 to BB), Top-Notch Young Talents Program of China of 2014 and Academic Frontier Youth Team of Huazhong University of Science and Technology (to LQZ); the Hubei Provincial Natural Science Foundation (2022CFA004 to LQ); the National Science & Technology Fundamental Resource Investigation Program of China (2018FY100903 to XPY); and Science and Technology Project Founded by the Education Department of Jiangxi Province (GJJ201834 to MXW). Jiangxi Provincial Health Commission Science and Technology Plan Project (202212021 to MXW and 202311506 to ZYC), and Jiangxi Provincial Administration of Traditional Chinese Medicine Science and Technology Plan Project (2022A322 to ZYC).

Author information

Author notes

  1. These authors contributed equally: Moxin Wu, Zhiying Chen, Min Jiang.

Authors and Affiliations

  1. Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China

    Moxin Wu

  2. Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China

    Moxin Wu, Zhiying Chen, Min Jiang, Bing Bao, Dongling Li & Xiaoping Yin

  3. Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China

    Zhiying Chen, Bing Bao, Dongling Li & Xiaoping Yin

  4. Department of Anesthesiology, Shanxi Bethune Hospital, Taiyuan, 030032, China

    Xueren Wang

  5. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xueren Wang

  6. Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Dan Liu

  7. Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ling-Qiang Zhu

Authors
  1. Moxin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiying Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bing Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongling Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoping Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueren Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ling-Qiang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The initial idea for this review was generated by LQZ and, DL, and the manuscript was written and revised by MXW, ZYC and MJ. In addition, MXW, MJ and BB contributed to illustration preparation; LQZ, XPY, DLL and ZYC edited the manuscript; DL, XRW, XPY and MXW read, reviewed, and approved the final manuscript. The final version of the manuscript was approved by all authors.

Corresponding authors

Correspondence to Xiaoping Yin, Xueren Wang, Dan Liu or Ling-Qiang Zhu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, M., Chen, Z., Jiang, M. et al. Friend or foe: role of pathological tau in neuronal death. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02024-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-023-02024-z

This article is cited by

Search

Advanced search

Quick links