VPS35 regulates tau phosphorylation and neuropathology in tauopathy


The vacuolar protein sorting 35 (VPS35) is a major component of the retromer recognition core complex which regulates intracellular protein sorting and trafficking. Deficiency in VPS35 by altering APP/Aβ metabolism has been linked to late-onset Alzheimer’s disease. Here we report that VPS35 is significantly reduced in Progressive Supra-nuclear Palsy and Picks’ disease, two distinct primary tauopathies. In vitro studies show that overexpression of VPS35 leads to a reduction of pathological tau in neuronal cells, whereas genetic silencing of VPS35 results in its accumulation. Mechanistically the availability of active cathepsin D mediates the effect of VPS35 on pathological tau accumulation. Moreover, in a relevant transgenic mouse model of tauopathy, down-regulation of VPS35 results in an exacerbation of motor and learning impairments as well as accumulation of pathological tau and loss of synaptic integrity. Taken together, our data identify VPS35 as a novel critical player in tau metabolism and neuropathology, and a new therapeutic target for human tauopathies.

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  1. 1.

    O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 2011;34:185–204.

    Article  Google Scholar 

  2. 2.

    Choy RW-Y, Chen Z, Schekman R. Amyloid precursor protein traffics from the cell surface via endosomes for amyloid beta production in the trans-Golgi network. Proc Natl Acad Sci USA. 2012;109:E2077–E2088.

    CAS  Article  Google Scholar 

  3. 3.

    Trousdale C, Kim K. Retromer: structure, function, and roles in mammalian disease. Eur J Cell Biol 2015;94:513–21.

    CAS  Article  Google Scholar 

  4. 4.

    Burd C, Cullen PJ. Retromer: a master conductor of endosome sorting. Cold Spring Harb Persp Biol. 2014;6:a01677.

    Google Scholar 

  5. 5.

    Wang S, Bellen HJ. The retromer complex in development and disease. Development. 2015;142:2392–6.

    CAS  Article  Google Scholar 

  6. 6.

    Temkin P, Lauffer B, Jager S, Cimermancic P, Krogan NJ, von Zastrow M. SNX27-mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signaling receptors. Nat Cell Biol 2011;13:715–21.

    Article  Google Scholar 

  7. 7.

    Nielsen MS, Gustafsen C, Madsen P, Nyengaard JR, Hermey G, et al. Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA. Mol Cell Biol 2007;27:6842–51.

    CAS  Article  Google Scholar 

  8. 8.

    Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, et al. Retromer binds the FANSHY soring motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci 2012;32:1467–80.

    CAS  Article  Google Scholar 

  9. 9.

    Small SA, Kent K, Pierce A, Leung C, Kang MS, et al. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol 2005;58:909–19.

    CAS  Article  Google Scholar 

  10. 10.

    Vardarajan BN, Bruesegem SY, Harbour ME, Inzelberg R, Friedland R, et al. Identification of Alzheimer’s disease-associated variants in genes that regulate retromer function. Neurobiol Aging. 2012;33:2231.e15–2231.e30.

    CAS  Article  Google Scholar 

  11. 11.

    Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, et al. Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation. Proc Natl Acad Sci USA. 2008;105:7327–32.

    CAS  Article  Google Scholar 

  12. 12.

    Wen L, Tang F-L, Hong Y, Luo S-W, Wang C-L, et al. VPS35 aploinsufficiency increases Alzheimer’s disease neuropathology. J Cell Biol 2011;195:765–79.

    CAS  Article  Google Scholar 

  13. 13.

    Chu J, Praticò D. The retromer complex system in a transgenic mouse model of AD: influence of age. Neurobiol Aging 2017;52:32–38.

    CAS  Article  Google Scholar 

  14. 14.

    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007;53:337–51.

    CAS  Article  Google Scholar 

  15. 15.

    Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE, Pratico D. Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice. Mol Neurodegener 2012;7:1.

    CAS  Article  Google Scholar 

  16. 16.

    Vagnozzi AN, Giannopoulos PF, Praticò D. Brain 5-lipoxygenase overexpression worsens memory, synaptic integrity, and tau pathology in the P301S mice. Aging Cell 2018;17:e12695.

    Article  Google Scholar 

  17. 17.

    Di Meco A, Lauretti E, Vagnozzi AN, Praticò D. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer’s disease mice. Neurobiol Aging. 2014;35:2458–64.

    Article  Google Scholar 

  18. 18.

    Li JG, Chu J, Barrero C, Merali S, Praticò D. Homocysteine exacerbates β‐amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol 2014;75:851–63.

    CAS  Article  Google Scholar 

  19. 19.

    Vagnozzi AN, Giannopoulos PF, Praticò D. The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. Transl Psychiatry 2017;18:1288.

    Article  Google Scholar 

  20. 20.

    Lauretti E, Li JG, Di Meco A, Praticò D. Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model. Transl Psychiatry 2017;7:e1020.

    CAS  Article  Google Scholar 

  21. 21.

    Li, JG, Chu, J, Praticò, D. Downregulation of autophagy by 12/15Lipoxygenase worsens the phenotype of an Alzheimer’s disease mouse model with plaques, tangles, and memory impairments. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0268-1.

  22. 22.

    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402–8.

    CAS  Article  Google Scholar 

  23. 23.

    Giannopoulos, PF, Chu, J, Praticò, D. Learning impairments, memory deficits, and neuropathology in aged tau transgenic mice are dependent on leukotrienes biosynthesis: role of the cdk5 kinase pathway. Mol Neurobiol. 2018. https://doi.org/10.1007/s12035-018-1124-7.

    Article  Google Scholar 

  24. 24.

    Miura E, Hasegawa T, Konno M, Suzuki M, Sugeno N, et al. VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson’s disease. Neurobiol Dis 2014;71:1–13.

    CAS  Article  Google Scholar 

  25. 25.

    Chu J, Li JG, Hoffman NE, Stough AM, Madesh M, Praticò D. Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence. Sci Rep 2015;5:11086.

    CAS  Article  Google Scholar 

  26. 26.

    Lauretti E, Praticò D. Glucose deprivation increases tau phosphorylation via P38 mitogen-activated protein kinase. Aging Cell. 2015;14:1067–74.

    CAS  Article  Google Scholar 

  27. 27.

    Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol 2014;10:443–9.

    CAS  Article  Google Scholar 

  28. 28.

    Kim E, Lee Y, Lee HJ, Kim JS, Song BS, et al. Implication of mouse VPS26b-VPS29-VPS35 retromer complex in sortilin trafficking. Biochem Biophys Res Commun 2010;403:167–71.

    CAS  Article  Google Scholar 

  29. 29.

    Bennett DA, Schneider JA, Wilson R, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol 2004;61:378–84.

    Article  Google Scholar 

  30. 30.

    Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 2016;8:338ra66.

    Article  Google Scholar 

  31. 31.

    Lee MJ, Lee JH, Rubinsztein DC. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Progr Neurobiol 2013;105:49–59.

    CAS  Article  Google Scholar 

  32. 32.

    Zhang Y, Chen X, Zhao Y, Ponnusamy M, Liu Y. The role of ubiquitin proteasomal system and autophagy-lysosomal pathway in Alzheimer’s disease. Rev Neurosci 2017;28:861–8.

    CAS  PubMed  Google Scholar 

  33. 33.

    Zang JY, Liu SJ, Li HL, Wang JZ. Microtubule-associated protein tau is a substrate of ATP/Mg (2+)-dependent proteasome protease system. J Neural Transm 2005;112:547–55.

    Article  Google Scholar 

  34. 34.

    Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, et al. Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci. 2018;27:119–1130.

    Google Scholar 

  35. 35.

    Schuur M, Ikram MA, van Swieten JC, Isaacs A, Vergeer-Drop JM, et al. Cathepsin D gene and the risk of Alzheimer’s disease: a population-based study and meta-analysis. Neurobiol Aging. 2011;32:1607–1614.

    CAS  Article  Google Scholar 

  36. 36.

    Chai, YL, Chong, JR, Weng, J, Howlett, D, Halsey, A, et al. Lysosomal cathepsin D is upregulated in Alzheimer’s disease neocortex and may be a marker for neurofibrillary degeneration. Brain Pathol. 2018. https://doi.org/10.1111/bpa.12631.

    Article  Google Scholar 

  37. 37.

    Follett J, Norwood SJ, Hamilton NA, Mohan M, Kovtun O. The VPS35 D620N mutation linked to Parkinson’s disease disrupts the cargo sorting function of retromer. Traffic. 2014;15:230–44.

    CAS  Article  Google Scholar 

  38. 38.

    Seaman MNJ. Cargo‐selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol. 2004;165:111–22.

    CAS  Article  Google Scholar 

  39. 39.

    Kenessey A, Nacharaju P, Ko L, Yen S. Degradation of Tau by lysosomal enzyme cathepsin D: implication for alzheimer neurofibrillary degeneration. J Neurochem 1997;69:2026–38.

    CAS  Article  Google Scholar 

  40. 40.

    Williams ET, Chen X, Moore DJ. VPS35, the retromer complex, and Parkinson’s disease. J Parkinsons Dis. 2017;7:219–33.

    CAS  Article  Google Scholar 

  41. 41.

    Li JG, Chiu J, Praticò D. Full recovery of the Alzheimer’s disease phenotype by gain of function of Vacuolar Protein Sorting 35. Mol. Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0364-x. (Epub ahead of print)

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Domenico Praticó is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s research. We would like to thank the patients and the families who have donated the brain tissues together with the University of Maryland Brain and Tissue Bank, the Human Brain and Spinal Fluid Resource Center (UCLA, Los Angeles, CA), and Harvard Brain Tissue Resource Center, McLean Hospital for providing post-mortem tissue through NIH NeuroBioBank. We would also like to thank Peter Davies for supplying the MC-1 antibody. This study was supported in part by grants from the National Institute of Health (AG055707, and AG056689).

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A.V., J.C., and D.P. designed the study, developed the experimental design, performed data analyses, and wrote the paper. A.V., J.C. and J.G.L., performed most of the experiments. R.R. and R.W contributed to the imaging studies. All authors discussed the results and commented on the manuscript.

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Correspondence to Domenico Praticò.

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Vagnozzi, A.N., Li, JG., Chiu, J. et al. VPS35 regulates tau phosphorylation and neuropathology in tauopathy. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0453-x

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