Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold naïve tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQIVYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK- or Cys322-targeting drugs have a reduced potency to cause aggregation of naïve tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK- or Cys322-targeting drugs may act as prophylactic agents against tau seeding.

Czech Advanced Technology and Research Institute Palacký University Olomouc Olomouc Czech Republic

Department of Medical Biophysics Faculty of Medicine and Dentistry Palacký University in Olomouc Olomouc Czech Republic

Department of Molecular Biochemistry and Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy

Department of Physical Chemistry Faculty of Science Palacký University Olomouc Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czech Republic

IT4Innovations VSB Technical University of Ostrava Ostrava Czech Republic

Zobrazit více v PubMed

Dujardin S, Commins C, Lathuiliere A, Beerepoot P, Fernandes AR, Kamath TV, De Los Santos MB, Klickstein N, Corjuc DL, Corjuc BT et al. (2020) Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease. Nat Med 26, 1256-1263.

DeVos SL, Corjuc BT, Oakley DH, Nobuhara CK, Bannon RN, Chase A, Commins C, Gonzalez JA, Dooley PM, Frosch MP et al. (2018) Synaptic tau seeding precedes tau pathology in human Alzheimer's disease brain. Front Neurosci 12, 267.

Vogel JW, Iturria-Medina Y, Strandberg OT, Smith R, Levitis E, Evans AC, Hansson O, Weiner M, Aisen P, Petersen R et al. (2020) Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease. Nat Commun 11, 2612.

Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M et al. (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11, 909-913.

Kaufman SK, Del Tredici K, Thomas TL, Braak H & Diamond MI (2018) Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer's disease and PART. Acta Neuropathol 136, 57-67.

Ossenkoppele R, Iaccarino L, Schonhaut DR, Brown JA, La Joie R, O'Neil JP, Janabi M, Baker SL, Kramer JH, Gorno-Tempini M-L et al. (2019) Tau covariance patterns in Alzheimer's disease patients match intrinsic connectivity networks in the healthy brain. Neuroimage Clin 23, 101848.

Franzmeier N, Rubinski A, Neitzel J, Kim Y, Damm A, Na DL, Kim HJ, Lyoo CH, Cho H, Finsterwalder S et al. (2019) Functional connectivity associated with tau levels in ageing, Alzheimer's, and small vessel disease. Brain 142, 1093-1107.

Cope TE, Rittman T, Borchert RJ, Jones PS, Vatansever D, Allinson K, Passamonti L, Vazquez Rodriguez P, Bevan-Jones WR, O'Brien JT et al. (2018) Tau burden and the functional connectome in Alzheimer's disease and progressive supranuclear palsy. Brain 141, 550-567.

La Joie R, Visani AV, Baker SL, Brown JA, Bourakova V, Cha J, Chaudhary K, Edwards L, Iaccarino L, Janabi M et al. (2020) Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med 12, eaau5732.

Congdon EE, Kim S, Bonchak J, Songrug T, Matzavinos A & Kuret J (2008) Nucleation-dependent tau filament formation: the importance of dimerisation and an estimation of elementary rate constants. J Biol Chem 283, 13806-13816.

Sonawane SK, Uversky VN & Chinnathambi S (2021) Baicalein inhibits heparin-induced Tau aggregation by initialising non-toxic Tau oligomer formation. Cell Commun Signal 19, 16.

Habchi J, Arosio P, Perni M, Costa AR, Yagi-Utsumi M, Joshi P, Chia S, Cohen SIA, Müller MBD, Linse S et al. (2016) An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease. Sci Adv 2, e1501244.

Seidler PM, Boyer DR, Murray KA, Yang TP, Bentzel M, Sawaya MR, Rosenberg G, Cascio D, Williams CK, Newell KL et al. (2019) Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples. J Biol Chem 294, 16451-16464.

Bhattacharya K, Rank KB, Evans DB & Sharma SK (2001) Role of cysteine-291 and cysteine-322 in the polymerisation of human tau into Alzheimer-like filaments. Biochem Biophys Res Comm 285, 20-26.

Kim D, Lim S, Haque MDM, Ryoo N, Hong HS, Rhim H, Lee D-E, Chang Y-T, Lee J-S, Cheong E et al. (2015) Identification of disulfide cross-linked tau dimer responsible for tau propagation. Sci Rep 5, 15231.

Soeda Y, Yoshikawa M, Almeida OFX, Sumioka A, Maeda S, Osada H, Kondoh Y, Saito A, Miyasaka T, Kimura T et al. (2015) Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups. Nat Commun 6, 10216.

Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S & Wolf PA (2012) Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ 344, e1442.

Musicco M, Adorni F, Di Santo S, Prinelli F, Pettenati C, Caltagirone C, Palmer K & Russo A (2013) Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology 81, 322-328.

Schmidt SAJ, Ording AG, Horváth-Puhó E, Sørensen HT & Henderson VW (2017) Non-melanoma skin cancer and risk of Alzheimer's disease and all-cause dementia. PLoS One 12, e0171527.

Frain L, Swanson D, Cho K, Gagnon D, Lu KP, Betensky RA & Driver J (2017) Association of cancer and Alzheimer's disease risk in a national cohort of veterans. Alzheimers Dement 13, 1364-1370.

Ospina-Romero M, Abdiwahab E, Kobayashi L, Filshtein T, Brenowitz WD, Mayeda ER & Glymour MM (2019) Rate of memory change before and after cancer diagnosis. JAMA Network Open 2, e196160.

Sun M, Wang Y, Sundquist J, Sundquist K & Ji J (2020) The association between cancer and dementia: a National Cohort Study in Sweden. Front Oncol 10, 73.

Lanni C, Masi M, Racchi M & Govoni S (2021) Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways. Mol Psychiatry 26, 280-295.

Mezencev R & Chernoff YO (2020) Risk of Alzheimer's disease in cancer patients: analysis of mortality data from the US SEER population-based registries. Cancers (Basel) 12, 796.

Kwok MK, Lin SL & Schooling CM (2018) Re-thinking Alzheimer's disease therapeutic targets using gene-based tests. EBioMedicine 37, 461-470.

Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM & Diamond MI (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA 111, E4376.

Johnston PA (2011) Redox cycling compounds generate H2O2 in HTS buffers containing strong reducing reagents-real hits or promiscuous artifacts? Curr Opin Chem Biol 15, 174-182.

Hudson SA, Ecroyd H, Kee TW & Carver JA (2009) The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds. FEBS J 276, 5960-5972.

Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D et al. (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27, 3650.

Ganguly P, Do TD, Larini L, LaPointe NE, Sercel AJ, Shade MF, Feinstein SC, Bowers MT & Shea J-E (2015) Tau assembly: the dominant role of PHF6 (VQIVYK) in microtubule binding region repeat R3. J Phys Chem B 119, 4582-4593.

Ghag G, Bhatt N, Cantu DV, Guerrero-Munoz MJ, Ellsworth A, Sengupta U & Kayed R (2018) Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. Protein Sci 27, 1901-1909.

Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q & Orr ME (2018) Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840.

Miyazaki Y, Mizumoto K, Dey G, Kudo T, Perrino J, Chen L, Meyer T & Wandless TJ (2016) A method to rapidly create protein aggregates in living cells. Nat Commun 7, 11689.

Margittai M & Langen R (2004) Template-assisted filament growth by parallel stacking of tau. Proc Natl Acad Sci USA 101, 10278.

Natale C, Barzago MM & Diomede L (2020) Caenorhabditis elegans models to investigate the mechanisms underlying tau toxicity in tauopathies. Brain Sci 10, 838.

Sandhof CA, Hoppe SO, Tittelmeier J & Nussbaum-Krammer C (2020) C. elegans models to study the propagation of prions and prion-like proteins. Biomolecules 10, 1188.

Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA, Evans K, Zhou G, Johnson NT, Hyman BT, Sorger PK et al. (2021) Machine learning identifies candidates for drug repurposing in Alzheimer's disease. Nat Commun 12, 1033.

Cummings J, Lee G, Ritter A & Zhong K (2018) Alzheimer's disease drug development pipeline: 2018. Alzheimers Dement (N Y) 4, 195-214.

Sun L-M, Chen H-J, Liang J-A & Kao C-H (2016) Long-term use of tamoxifen reduces the risk of dementia: a nationwide population-based cohort study. QJM 109, 103-109.

Brunden KR, Yao Y, Potuzak JS, Ferrer NI, Ballatore C, James MJ, Hogan A-ML, Trojanowski JQ, Smith Iii AB & Lee VMY (2011) The characterisation of microtubule-stabilising drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies. Pharmacol Res 63, 341-351.

Huang L, Lin J, Xiang S, Zhao K, Yu J, Zheng J, Xu D, Mak S, Hu S, Nirasha S et al. (2016) Sunitinib, a clinically used anticancer drug, is a potent AChE inhibitor and attenuates cognitive impairments in mice. ACS Chem Neurosci 7, 1047-1056.

Cramer PE, Cirrito JR, Wesson DW, Daniel Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ et al. (2012) ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503-1506.

O'Hare E, Jeggo R, Kim E-M, Barbour B, Walczak J-S, Palmer P, Lyons T, Page D, Hanna D, Meara JR et al. (2016) Lack of support for bexarotene as a treatment for Alzheimer's disease. Neuropharmacology 100, 124-130.

Hayes CD, Dey D, Palavicini JP, Wang H, Patkar KA, Minond D, Nefzi A & Lakshmana MK (2013) Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine. BMC Med 11, 81.

Chu J, Lauretti E, Craige CP & Praticò D (2014) Pharmacological modulation of GSAP reduces amyloid-β levels and tau phosphorylation in a mouse model of Alzheimer's disease with plaques and tangles. J Alzheimers Dis 41, 729-737.

Hernandez I, Luna G, Rauch JN, Reis SA, Giroux M, Karch CM, Boctor D, Sibih YE, Storm NJ, Diaz A et al. (2019) A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med 11, eaat3005.

Bulic B, Pickhardt M, Schmidt B, Mandelkow E-M, Waldmann H & Mandelkow E (2009) Development of tau aggregation inhibitors for Alzheimer’s disease. Angew Chem Int Ed 48, 1740-1752.

Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muñoz MJ, Jackson GR & Kayed R (2010) Preparation and characterisation of neurotoxic tau oligomers. Biochemistry 49, 10039-10041.

Kaniyappan S, Chandupatla RR, Mandelkow E-M & Mandelkow E (2017) Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimers Dement 13, 1270-1291.

Flach K, Hilbrich I, Schiffmann A, Gärtner U, Krüger M, Leonhardt M, Waschipky H, Wick L, Arendt T & Holzer M (2012) Tau oligomers impair artificial membrane integrity and cellular viability *. J Biol Chem 287, 43223-43233.

Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24, 1246-1256.

Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow E-M, Diamond MI, Lee VM-Y et al. (2011) In Vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31, 13110.

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.

Nečas D & Klapetek P (2012) Gwyddion: an open-source software for SPM data analysis. Cent Eur J Phys 10, 181-188.

Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M & Scheres SHW (2017) Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547, 185-190.

Šali A & Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234, 779-815.

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H et al. (2016) F Gaussian 09, Revision A.02. Gaussian, Inc., Wallingford, CT.

Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM et al. (2010) AMBER 11. University of California, San Francisco, CA.

Bayly CI, Cieplak P, Cornell W & Kollman PA (1993) A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J Phys Chem 97, 10269-10280.

Trott O & Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimisation, and multithreading. J Comput Chem 31, 455-461.

Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE & Simmerling C (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11, 3696-3713.

Ryckaert J-P, Ciccotti G & Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23, 327-341.

Allen MP & Tildesley DJ (1991) Computer Simulation of Liquids. Oxford University Press, New York, NY.

Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A & Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81, 3684-3690.

Darden T, York D & Pedersen L (1993) Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J Chem Phys 98, 10089-10092.

Ester M, Kriegel H-P, Sander J & Xiaowei X (1996) A density-based algorithm for discovering clusters in large spatial databases with noise. In In Proceedings of the Second International Conference on Knowledge Discovery and Data Mining (Simoudis E, Han J & Fayyad U, eds), pp. 226-231. AAAI Press.

Seidler PM, Boyer DR, Rodriguez JA, Sawaya MR, Cascio D, Murray K, Gonen T & Eisenberg DS (2018) Structure-based inhibitors of tau aggregation. Nat Chem 10, 170-176.

Diomede L, Rognoni P, Lavatelli F, Romeo M, del Favero E, Cantù L, Ghibaudi E, di Fonzo A, Corbelli A, Fiordaliso F et al. (2014) A Caenorhabditis elegans-based assay recognises immunoglobulin light chains causing heart amyloidosis. Blood 123, 3543.

Inflammation, Autoimmunity and Neurodegenerative Diseases, Therapeutics and Beyond