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APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology

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Abstract

Alzheimer’s disease (AD), as the most common type of dementia, has two pathological hallmarks, extracellular senile plaques composed of β-amyloid peptides and intracellular neurofibrillary tangles containing phosphorylated-tau protein. Amyloid precursor protein (APP) and tau each play central roles in AD, although how APP and tau interact and synergize in the disease process is largely unknown. Here, we showed that soluble tau interacts with the N-terminal of APP in vitro in cell-free and cell culture systems, which can be further confirmed in vivo in the brain of 3XTg-AD mouse. In addition, APP is involved in the cellular uptake of tau through endocytosis. APP knockdown or N-terminal APP-specific antagonist 6KApoEp can prevent tau uptake in vitro, resulting in an extracellular tau accumulation in cultured neuronal cells. Interestingly, in APP/PS1 transgenic mouse brain, the overexpression of APP exacerbated tau propagation. Moreover, in the human tau transgenic mouse brain, overexpression of APP promotes tau phosphorylation, which is significantly remediated by 6KapoEp. All these results demonstrate the important role of APP in the tauopathy of AD. Targeting the pathological interaction of N-terminal APP with tau may provide an important therapeutic strategy for AD.

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The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

References

  1. Anand R, Gill KD, Mahdi AA (2014) Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology 76 Pt A:27–50

    Article  CAS  PubMed  Google Scholar 

  2. Kumar A, Singh A, Ekavali (2015) A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep 67:195–203

  3. Deyts C, Thinakaran G, Parent AT (2016) APP receptor? To be or not to be. Trends Pharmacol Sci 37:390–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Obregon D, Hou H, Deng J, Giunta B, Tian J et al (2012) Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation. Nat Commun 3:777

    Article  PubMed  Google Scholar 

  5. van der Kant R, Goldstein LS (2015) Cellular functions of the amyloid precursor protein from development to dementia. Dev Cell 32:502–515

    Article  PubMed  Google Scholar 

  6. Ayers JI, Giasson BI, Borchelt DR (2018) Prion-like spreading in tauopathies. Biol Psychiatry 83:337–346

    Article  CAS  PubMed  Google Scholar 

  7. Pérez M, Cuadros R, Medina M (2018) Tau assembly into filaments. Methods Mol Biol 1779:447–461

    Article  PubMed  Google Scholar 

  8. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  9. Simón D, García-García E, Royo F, Falcón-Pérez JM, Avila J (2012) Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett 586(1):47–54

    Article  PubMed  Google Scholar 

  10. Saman S, Lee NC, Inoyo I, Jin J, Li Z et al (2014) Proteins recruited to exosomes by tau overexpression implicate novel cellular mechanisms linking tau secretion with Alzheimer’s disease. J Alzheimers Dis 40(Suppl 1):S47-70

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ruan Z, Pathak D, Venkatesan Kalavai S, Yoshii-Kitahara A, Muraoka S et al (2020) Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain 144:288–309

    Article  PubMed Central  Google Scholar 

  12. Annadurai N, De Sanctis JB, Hajdúch M, Das V (2021) Tau secretion and propagation: perspectives for potential preventive interventions in Alzheimer’s disease and other tauopathies. Exp Neurol 343:113756

    Article  CAS  PubMed  Google Scholar 

  13. Merezhko M, Brunello CA, Yan X, Vihinen H, Jokitalo E et al (2018) Secretion of tau via an unconventional non-vesicular mechanism. Cell Rep 25(8):2027-2035.e4

    Article  CAS  PubMed  Google Scholar 

  14. Hellén M, Bhattacharjee A, Uronen RL, Huttunen HJ (2021) Membrane interaction and disulphide-bridge formation in the unconventional secretion of tau. Biosci Rep 41(8):BSR20210148

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zheng T, Wu X, Wei X, Wang M, Zhang B (2018) The release and transmission of amyloid precursor protein via exosomes. Neurochem Int 114:18–25

    Article  CAS  PubMed  Google Scholar 

  16. Laulagnier K, Javalet C, Hemming FJ, Chivet M, Lachenal G et al (2018) Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons. Cell Mol Life Sci 75:757–773

    Article  CAS  PubMed  Google Scholar 

  17. Barbato C, Canu N, Zambrano N, Serafino A, Minopoli G et al (2005) Interaction of tau with Fe65 links tau to APP. Neurobiol Dis 18:399–408

    Article  CAS  PubMed  Google Scholar 

  18. Giaccone G, Pedrotti B, Migheli A, Verga L, Perez J et al (1996) beta PP and tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer’s disease. Am J Pathol 148:79–87

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Smith MA, Siedlak SL, Richey PL, Mulvihill P, Ghiso J et al (1995) Tau protein directly interacts with the amyloid beta-protein precursor: implications for Alzheimer’s disease. Nat Med 1:365–369

    Article  CAS  PubMed  Google Scholar 

  20. Takahashi M, Miyata H, Kametani F, Nonaka T, Akiyama H et al (2015) Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau. Acta Neuropathol 129:895–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515:274–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moore S, Evans LD, Andersson T, Portelius E, Smith J et al (2015) APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep 11:689–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Puzzo D, Piacentini R, Fa M, Gulisano W, Li Puma DD et al (2017) LTP and memory impairment caused by extracellular Abeta and tau oligomers is APP-dependent. Elife 6:e26991

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G et al (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320:1446–1452

    Article  CAS  PubMed  Google Scholar 

  25. Wilcock DM, Griffin WS (2013) Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflamm 10:84

    Article  CAS  Google Scholar 

  26. Sawmiller D, Habib A, Hou H, Mori T, Fan A et al (2019) A novel apolipoprotein E antagonist functionally blocks apolipoprotein E interaction with N-terminal amyloid precursor protein, reduces beta-amyloid-associated pathology, and improves cognition. Biol Psychiatry 86:208–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rauch JN, Luna G, Guzman E, Audouard M, Challis C et al (2020) LRP1 is a master regulator of tau uptake and spread. Nature 580(7803):381–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cooper JM, Lathuiliere A, Migliorini M, Arai AL, Wani MM et al (2021) Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism. J Biol Chem 296:100715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL et al (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590

    Article  CAS  PubMed  Google Scholar 

  30. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM et al (2000) High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Multhaup G, Huber O, Buee L, Galas MC (2015) Amyloid precursor protein (APP) metabolites APP intracellular fragment (AICD), Abeta42, and tau in nuclear roles. J Biol Chem 290:23515–23522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mattson MP, Arumugam TV (2018) Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab 27:1176–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P et al (2010) Tau reduction prevents Abeta-induced defects in axonal transport. Science 330:198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ovchinnikov DA, Korn O, Virshup I, Wells CA, Wolvetang EJ (2018) The impact of APP on Alzheimer-like pathogenesis and gene expression in down syndrome iPSC-derived neurons. Stem Cell Rep 11:32–42

    Article  CAS  Google Scholar 

  36. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754

    Article  CAS  PubMed  Google Scholar 

  37. Leroy K, Ando K, Laporte V, Dedecker R, Suain V et al (2012) Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am J Pathol 181:1928–1940

    Article  CAS  PubMed  Google Scholar 

  38. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J et al (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci 31:700–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS et al (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 9:eaag0481

    Article  PubMed  PubMed Central  Google Scholar 

  40. DeVos SL, Corjuc BT, Commins C, Dujardin S, Bannon RN et al (2018) Tau reduction in the presence of amyloid-beta prevents tau pathology and neuronal death in vivo. Brain 141:2194–2212

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sebastián-Serrano Á, de Diego-García L, Díaz-Hernández M (2018) The neurotoxic role of extracellular tau protein. Int J Mol Sci 19:998

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gómez-Ramos A, Díaz-Hernández M, Cuadros R, Hernández F, Avila J (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580:4842–4850

    Article  PubMed  Google Scholar 

  43. Michel CH, Kumar S, Pinotsi D, Tunnacliffe A, St George-Hyslop P et al (2014) Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J Biol Chem 289:956–967

    Article  CAS  PubMed  Google Scholar 

  44. Wei Y, Liu M, Wang D (2022) The propagation mechanisms of extracellular tau in Alzheimer’s disease. J Neurol 269:1164–1181

    Article  PubMed  Google Scholar 

  45. Patel TK, Habimana-Griffin L, Gao X, Xu B, Achilefu S et al (2019) Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol Neurodegener 14:11

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I et al (2022) Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med 219:e20211275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jiang S, Bhaskar K (2020) Degradation and transmission of tau by autophagic-endolysosomal networks and potential therapeutic targets for tauopathy. Front Mol Neurosci 13:586731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Congdon EE, Jiang Y, Sigurdsson EM (2022) Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly. Semin Cell Dev Biol 126:125–137

    Article  CAS  PubMed  Google Scholar 

  49. Linghu C, Johnson SL, Valdes PA, Shemesh OA, Park WM et al (2020) Spatial multiplexing of fluorescent reporters for imaging signaling network dynamics. Cell 183:1682-1698.e24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL et al (2013) Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499:295–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fletcher JM, Boyle AL, Bruning M, Bartlett GJ, Vincent TL et al (2012) A basis set of de novo coiled-coil peptide oligomers for rational protein design and synthetic biology. ACS Synth Biol 1:240–250

    Article  CAS  PubMed  Google Scholar 

  52. Grigoryan G, Kim YH, Acharya R, Axelrod K, Jain RM et al (2011) Computational design of virus-like protein assemblies on carbon nanotube surfaces. Science 332:1071–1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gradišar H, Božič S, Doles T, Vengust D, Hafner-Bratkovič I et al (2013) Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments. Nat Chem Biol 9:362–366

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hu W, Zhang X, Tung YC, Xie S, Liu F et al (2016) Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement 12(10):1066–1077

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Drs. Mark P. Mattson, Takashi Mori, Darrell Sawmiller, Ahsan Habib for their helpful discussion. We would like to thank Dr. Lucy Hou and Mr. Jun Tian for their technical supporting.

Funding

This study was supported by the High-level Talent Foundation of Guizhou Medical University (YJ19017, HY2020, J. T.), National Natural Science Foundation of China (NSFC) (82171423, 82060211, J. T.), Anyu Biopharmaceutics, Inc., Hangzhou (06202010204, J. T.), the National Key Technologies R & D Program of China during the 9th Five-Year Plan Period [4008 (2019), J. T.], National Natural Science Foundation of China Project for Innovative Talents (HS22102, J. T.), Guizhou Provincial Health Commission (gzwjkj2019-1-044, J. C.), Scientific Research Project of Higher Education Institutions in Guizhou Province [192(2022), J.C.], Guizhou Province Basic Research Program (Natural Science) Project [Qiankehe Foundation-ZK (2023) General 301, J.C.], and the Guizhou Provincial Health Commission (WT19006, J. C.).

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Author notes

  1. Jiang Chen, Anran Fan and Song Li contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Endemic and Ethnic Diseases, Laboratory of Molecular Biology, Ministry of Education, Guizhou Medical University, Guiyang, 550025, Guizhou, China

    Jiang Chen, Yan Xiao, Yanlin Fu, Jun-Sheng Chen & Jun Tan

  2. Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center, Ministry of Education, Guizhou Medical University, Guiyang, 550025, Guizhou, China

    Anran Fan

  3. First Affiliated Hospital of Dalian Medical University, Dalian, 116021, Liaoning, China

    Song Li

  4. Department of Gynecology, Guizhou Provincial People’s Hospital, Guiyang, 550025, Guizhou, China

    Dan Zi

  5. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310015, Zhejiang, China

    Ling-Hui Zeng & Jun Tan

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  1. Jiang Chen
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Contributions

JC, AF, SL, YF JSC and YX performed the experiments, assisted in the design of the study, analyzed the data and drafted the manuscript. JC YF and JSC performed IHC, WB, IP and ELISA, and contributed to data analysis. AF, LZ, DZ, YX and XX assisted in the design of the study, manuscript composition and editing. JT and SL designed and supervised the study, analyzed the data and assisted in the composition and editing of the manuscript. All the authors discussed the results and commented on the final version of the manuscript.

Corresponding author

Correspondence to Jun Tan.

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Conflict of interest

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Jun Tan (J.T.) is a cofounder for Anyu Biopharmaceutics, Inc. J.C., S.L., D.Z. and J.T. are inventors on a patent application submitted by Anyu Biopharmaceutics, Inc. All other authors report no biomedical financial interests or potential conflicts of interest.

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All mice were housed and maintained in the Animal Facility at Guizhou Medical University, and all experiments were conducted in compliance with protocols approved by Guizhou Medical University Institutional Animal Care and Use Committee.

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Chen, J., Fan, A., Li, S. et al. APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology. Cell. Mol. Life Sci. 80, 123 (2023). https://doi.org/10.1007/s00018-023-04774-z

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