The neurotoxicity of phosphorylated tau protein (P-tau) and mitochondrial dysfunction play a significant role in the pathophysiology of Alzheimer's disease (AD). In vitro studies of the effects of P-tau oligomers on mitochondrial bioenergetics and reactive oxygen species production will allow us to evaluate the direct influence of P-tau on mitochondrial function. We measured the in vitro effect of P-tau oligomers on oxygen consumption and hydrogen peroxide production in isolated brain mitochondria. An appropriate combination of specific substrates and inhibitors of the phosphorylation pathway enabled the measurement and functional analysis of the effect of P-tau on mitochondrial respiration in defined coupling control states achieved in complex I-, II-, and I&II-linked electron transfer pathways. At submicromolar P-tau concentrations, we found no significant effect of P-tau on either mitochondrial respiration or hydrogen peroxide production in different respiratory states. The titration of P-tau showed a nonsignificant dose-dependent decrease in hydrogen peroxide production for complex I- and I&II-linked pathways. An insignificant in vitro effect of P-tau oligomers on both mitochondrial respiration and hydrogen peroxide production indicates that P-tau-induced mitochondrial dysfunction in AD is not due to direct effects of P-tau on the efficiency of the electron transport chain and on the production of reactive oxygen species.

Department of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague 120 00 Prague Czech Republic

Department of Psychiatry 1st Faculty of Medicine Charles University and General University Hospital Prague Ke Karlovu 11 120 00 Prague Czech Republic

Zobrazit více v PubMed

Zia A., Pourbagher-Shahri A.M., Farkhondeh T., Samarghandian S. Molecular and cellular pathways contributing to brain aging. Behav. Brain Funct. 2021;17:6. doi: 10.1186/s12993-021-00179-9. PubMed DOI PMC

Grimm A., Eckert A. Brain aging and neurodegeneration: From a mitochondrial point of view. J. Neurochem. 2017;143:418–431. doi: 10.1111/jnc.14037. PubMed DOI PMC

Fišar Z., Hroudová J., Zvěřová M., Jirák R., Raboch J., Kitzlerová E. Age-dependent alterations in platelet mitochondrial respiration. Biomedicines. 2023;11:1564. doi: 10.3390/biomedicines11061564. PubMed DOI PMC

Pereira C.F., Santos A.E., Moreira P.I., Pereira A.C., Sousa F.J., Cardoso S.M., Cruz M.T. Is Alzheimer’s disease an inflammasomopathy? Ageing Res. Rev. 2019;56:100966. doi: 10.1016/j.arr.2019.100966. PubMed DOI

2024 Alzheimer’s disease facts and figures. Alzheimers Dement. 2024;20:3708–3821. doi: 10.1002/alz.13809. PubMed DOI PMC

Ma C., Hong F., Yang S. Amyloidosis in Alzheimer’s disease: Pathogeny, etiology, and related therapeutic directions. Molecules. 2022;27:1210. doi: 10.3390/molecules27041210. PubMed DOI PMC

Devi G. The tauopathies. Handb. Clin. Neurol. 2023;196:251–265. doi: 10.1016/B978-0-323-98817-9.00015-6. PubMed DOI

Blömeke L., Rehn F., Kraemer-Schulien V., Kutzsche J., Pils M., Bujnicki T., Lewczuk P., Kornhuber J., Freiesleben S.D., Schneider L.S., et al. Aβ oligomers peak in early stages of Alzheimer’s disease preceding tau pathology. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2024;16:e12589. doi: 10.1002/dad2.12589. PubMed DOI PMC

Wang C., Zong S., Cui X., Wang X., Wu S., Wang L., Liu Y., Lu Z. The effects of microglia-associated neuroinflammation on Alzheimer’s disease. Front. Immunol. 2023;14:1117172. doi: 10.3389/fimmu.2023.1117172. PubMed DOI PMC

Liu Z., Zhou T., Ziegler A.C., Dimitrion P., Zuo L. Oxidative stress in neurodegenerative diseases: From molecular mechanisms to clinical applications. Oxid. Med. Cell Longev. 2017;2017:2525967. doi: 10.1155/2017/2525967. PubMed DOI PMC

Bhatia V., Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer’s disease. J. Neurol. Sci. 2021;421:117253. doi: 10.1016/j.jns.2020.117253. PubMed DOI

Liu Z., Li T., Li P., Wei N., Zhao Z., Liang H., Ji X., Chen W., Xue M., Wei J. The ambiguous relationship of oxidative stress, tau hyperphosphorylation, and autophagy dysfunction in Alzheimer’s disease. Oxid. Med. Cell Longev. 2015;2015:352723. doi: 10.1155/2015/352723. PubMed DOI PMC

Leuzy A., Chiotis K., Lemoine L., Gillberg P.G., Almkvist O., Rodriguez-Vieitez E., Nordberg A. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol. Psychiatry. 2019;24:1112–1134. doi: 10.1038/s41380-018-0342-8. PubMed DOI PMC

Medina M., Hernandez F., Avila J. New features about tau function and dysfunction. Biomolecules. 2016;6:21. doi: 10.3390/biom6020021. PubMed DOI PMC

Torres A.K., Jara C., Park-Kang H.S., Polanco C.M., Tapia D., Alarcon F., de la Pena A., Llanquinao J., Vargas-Mardones G., Indo J.A., et al. Synaptic mitochondria: An early target of amyloid-beta and tau in Alzheimer’s disease. J. Alzheimers Dis. 2021;84:1391–1414. doi: 10.3233/JAD-215139. PubMed DOI

Cheng Y., Bai F. The association of tau with mitochondrial dysfunction in Alzheimer’s disease. Front. Neurosci. 2018;12:163. doi: 10.3389/fnins.2018.00163. PubMed DOI PMC

Manczak M., Reddy P.H. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: Implications for mitochondrial dysfunction and neuronal damage. Hum. Mol. Genet. 2012;21:2538–2547. doi: 10.1093/hmg/dds072. PubMed DOI PMC

Supnet C., Bezprozvanny I. The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium. 2010;47:183–189. doi: 10.1016/j.ceca.2009.12.014. PubMed DOI PMC

Musiek E.S., Holtzman D.M. Three dimensions of the amyloid hypothesis: Time, space and ‘wingmen’. Nat. Neurosci. 2015;18:800–806. doi: 10.1038/nn.4018. PubMed DOI PMC

Swerdlow R.H. The mitochondrial hypothesis: Dysfunction, bioenergetic defects, and the metabolic link to Alzheimer’s disease. Int. Rev. Neurobiol. 2020;154:207–233. doi: 10.1016/bs.irn.2020.01.008. PubMed DOI PMC

Karran E., De Strooper B. The amyloid cascade hypothesis: Are we poised for success or failure? J. Neurochem. 2016;139((Suppl. S2)):237–252. doi: 10.1111/jnc.13632. PubMed DOI

Liu P.P., Xie Y., Meng X.Y., Kang J.S. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct. Target. Ther. 2019;4:29. doi: 10.1038/s41392-019-0063-8. PubMed DOI PMC

Swerdlow R.H. Mitochondria and mitochondrial cascades in Alzheimer’s disease. J. Alzheimers Dis. 2018;62:1403–1416. doi: 10.3233/JAD-170585. PubMed DOI PMC

Fišar Z. Linking the amyloid, tau, and mitochondrial hypotheses of Alzheimer’s disease and identifying promising drug targets. Biomolecules. 2022;12:1676. doi: 10.3390/biom12111676. PubMed DOI PMC

Bonda D.J., Wang X., Lee H.G., Smith M.A., Perry G., Zhu X. Neuronal failure in Alzheimer’s disease: A view through the oxidative stress looking-glass. Neurosci. Bull. 2014;30:243–252. doi: 10.1007/s12264-013-1424-x. PubMed DOI PMC

Tapia-Rojas C., Cabezas-Opazo F., Deaton C.A., Vergara E.H., Johnson G.V.W., Quintanilla R.A. It’s all about tau. Prog. Neurobiol. 2019;175:54–76. doi: 10.1016/j.pneurobio.2018.12.005. PubMed DOI PMC

Liu F., Grundke-Iqbal I., Iqbal K., Gong C.X. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 2005;22:1942–1950. doi: 10.1111/j.1460-9568.2005.04391.x. PubMed DOI

Leroy K., Yilmaz Z., Brion J.P. Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol. Appl. Neurobiol. 2007;33:43–55. doi: 10.1111/j.1365-2990.2006.00795.x. PubMed DOI

Hooper C., Killick R., Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J. Neurochem. 2008;104:1433–1439. doi: 10.1111/j.1471-4159.2007.05194.x. PubMed DOI PMC

Kosik K.S., Joachim C.L., Selkoe D.J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. USA. 1986;83:4044–4048. doi: 10.1073/pnas.83.11.4044. PubMed DOI PMC

Arnsten A.F.T., Datta D., Del Tredici K., Braak H. Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer’s disease. Alzheimers Dement. 2021;17:115–124. doi: 10.1002/alz.12192. PubMed DOI PMC

Kametani F., Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front. Neurosci. 2018;12:25. doi: 10.3389/fnins.2018.00025. PubMed DOI PMC

Martin L., Latypova X., Terro F. Post-translational modifications of tau protein: Implications for Alzheimer’s disease. Neurochem. Int. 2011;58:458–471. doi: 10.1016/j.neuint.2010.12.023. PubMed DOI

Takashima A. Tauopathies and tau oligomers. J. Alzheimers Dis. 2013;37:565–568. doi: 10.3233/JAD-130653. PubMed DOI

Ward S.M., Himmelstein D.S., Lancia J.K., Binder L.I. Tau oligomers and tau toxicity in neurodegenerative disease. Biochem. Soc. Trans. 2012;40:667–671. doi: 10.1042/BST20120134. PubMed DOI PMC

Cardenas-Aguayo Mdel C., Gomez-Virgilio L., DeRosa S., Meraz-Rios M.A. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem. Neurosci. 2014;5:1178–1191. doi: 10.1021/cn500148z. PubMed DOI

Cowan C.M., Mudher A. Are tau aggregates toxic or protective in tauopathies? Front. Neurol. 2013;4:114. doi: 10.3389/fneur.2013.00114. PubMed DOI PMC

Szabo L., Eckert A., Grimm A. Insights into disease-associated tau impact on mitochondria. Int. J. Mol. Sci. 2020;21:6344. doi: 10.3390/ijms21176344. PubMed DOI PMC

Lasagna-Reeves C.A., Sengupta U., Castillo-Carranza D., Gerson J.E., Guerrero-Munoz M., Troncoso J.C., Jackson G.R., Kayed R. The formation of tau pore-like structures is prevalent and cell specific: Possible implications for the disease phenotypes. Acta Neuropathol. Commun. 2014;2:56. doi: 10.1186/2051-5960-2-56. PubMed DOI PMC

Clavaguera F., Akatsu H., Fraser G., Crowther R.A., Frank S., Hench J., Probst A., Winkler D.T., Reichwald J., Staufenbiel M., et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. USA. 2013;110:9535–9540. doi: 10.1073/pnas.1301175110. PubMed DOI PMC

Lewis J., Dickson D.W. Propagation of tau pathology: Hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol. 2016;131:27–48. doi: 10.1007/s00401-015-1507-z. PubMed DOI

Bloom G.S. Amyloid-beta and tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71:505–508. doi: 10.1001/jamaneurol.2013.5847. PubMed DOI

Karikari T.K., Nagel D.A., Grainger A., Clarke-Bland C., Hill E.J., Moffat K.G. Preparation of stable tau oligomers for cellular and biochemical studies. Anal. Biochem. 2019;566:67–74. doi: 10.1016/j.ab.2018.10.013. PubMed DOI PMC

Cieri D., Vicario M., Vallese F., D’Orsi B., Berto P., Grinzato A., Catoni C., De Stefani D., Rizzuto R., Brini M., et al. Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca(2+) handling. Biochim. Biophys. Acta Mol. Basis Dis. 2018;1864:3247–3256. doi: 10.1016/j.bbadis.2018.07.011. PubMed DOI

Shafiei S.S., Guerrero-Munoz M.J., Castillo-Carranza D.L. Tau oligomers: Cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 2017;9:83. doi: 10.3389/fnagi.2017.00083. PubMed DOI PMC

Paradies G., Paradies V., De Benedictis V., Ruggiero F.M., Petrosillo G. Functional role of cardiolipin in mitochondrial bioenergetics. Biochim. Biophys. Acta. 2014;1837:408–417. doi: 10.1016/j.bbabio.2013.10.006. PubMed DOI

Camilleri A., Ghio S., Caruana M., Weckbecker D., Schmidt F., Kamp F., Leonov A., Ryazanov S., Griesinger C., Giese A., et al. Tau-induced mitochondrial membrane perturbation is dependent upon cardiolipin. Biochim. Biophys. Acta Biomembr. 2020;1862:183064. doi: 10.1016/j.bbamem.2019.183064. PubMed DOI

Lasagna-Reeves C.A., Castillo-Carranza D.L., Sengupta U., Clos A.L., Jackson G.R., Kayed R. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol. Neurodegener. 2011;6:39. doi: 10.1186/1750-1326-6-39. PubMed DOI PMC

Britti E., Ros J., Esteras N., Abramov A.Y. Tau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calcium-induced cell death. Cell Calcium. 2020;86:102150. doi: 10.1016/j.ceca.2019.102150. PubMed DOI

Eckert A., Nisbet R., Grimm A., Gotz J. March separate, strike together—Role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer’s disease. Biochim. Biophys. Acta. 2014;1842:1258–1266. doi: 10.1016/j.bbadis.2013.08.013. PubMed DOI

Rhein V., Song X., Wiesner A., Ittner L.M., Baysang G., Meier F., Ozmen L., Bluethmann H., Drose S., Brandt U., et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc. Natl. Acad. Sci. USA. 2009;106:20057–20062. doi: 10.1073/pnas.0905529106. PubMed DOI PMC

David D.C., Hauptmann S., Scherping I., Schuessel K., Keil U., Rizzu P., Ravid R., Drose S., Brandt U., Muller W.E., et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 2005;280:23802–23814. doi: 10.1074/jbc.M500356200. PubMed DOI

Schulz K.L., Eckert A., Rhein V., Mai S., Haase W., Reichert A.S., Jendrach M., Muller W.E., Leuner K. A new link to mitochondrial impairment in tauopathies. Mol. Neurobiol. 2012;46:205–216. doi: 10.1007/s12035-012-8308-3. PubMed DOI

Grimm A., Biliouris E.E., Lang U.E., Gotz J., Mensah-Nyagan A.G., Eckert A. Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-beta or hyperphosphorylated tau protein. Cell Mol. Life Sci. 2016;73:201–215. doi: 10.1007/s00018-015-1988-x. PubMed DOI PMC

Grimm A., Lejri I., Halle F., Schmitt M., Gotz J., Bihel F., Eckert A. Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies. J. Neuroendocr. 2020;32:e12796. doi: 10.1111/jne.12796. PubMed DOI PMC

Eckert A., Schmitt K., Gotz J. Mitochondrial dysfunction—The beginning of the end in Alzheimer’s disease? Separate and synergistic modes of tau and amyloid-beta toxicity. Alzheimers Res. Ther. 2011;3:15. doi: 10.1186/alzrt74. PubMed DOI PMC

Perez M.J., Jara C., Quintanilla R.A. Contribution of tau pathology to mitochondrial impairment in neurodegeneration. Front. Neurosci. 2018;12:441. doi: 10.3389/fnins.2018.00441. PubMed DOI PMC

Plascencia-Villa G., Perry G. Roles of oxidative stress in synaptic dysfunction and neuronal cell death in Alzheimer’s disease. Antioxidants. 2023;12:1628. doi: 10.3390/antiox12081628. PubMed DOI PMC

Li X.C., Hu Y., Wang Z.H., Luo Y., Zhang Y., Liu X.P., Feng Q., Wang Q., Ye K., Liu G.P., et al. Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci. Rep. 2016;6:24756. doi: 10.1038/srep24756. PubMed DOI PMC

Atlante A., Amadoro G., Bobba A., de Bari L., Corsetti V., Pappalardo G., Marra E., Calissano P., Passarella S. A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator. Biochim. Biophys. Acta. 2008;1777:1289–1300. doi: 10.1016/j.bbabio.2008.07.004. PubMed DOI

Pesta D., Gnaiger E. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol. Biol. 2012;810:25–58. doi: 10.1007/978-1-61779-382-0_3. PubMed DOI

Kuznetsov A.V., Brandacher G., Steurer W., Margreiter R., Gnaiger E. Isolated rat heart mitochondria and whole rat heart as models for mitochondrial cold ischemia-reperfusion injury. Transpl. Proc. 2000;32:45. doi: 10.1016/S0041-1345(99)00869-6. PubMed DOI

Hroudová J., Fišar Z. Assessment of the effects of drugs on mitochondrial respiration. Methods Mol. Biol. 2021;2277:133–142. doi: 10.1007/978-1-0716-1270-5_9. PubMed DOI

Fišar Z., Hroudová J. Pig brain mitochondria as a biological model for study of mitochondrial respiration. Folia Biol. 2016;62:15–25. doi: 10.14712/fb2016062010015. PubMed DOI

Krumschnabel G., Fontana-Ayoub M., Sumbalova Z., Heidler J., Gauper K., Fasching M., Gnaiger E. Simultaneous high-resolution measurement of mitochondrial respiration and hydrogen peroxide production. Methods Mol. Biol. 2015;1264:245–261. doi: 10.1007/978-1-4939-2257-4_22. PubMed DOI

Fišar Z., Hroudová J., Singh N., Kopřivová A., Macečková D. Effect of simvastatin, coenzyme Q10, resveratrol, acetylcysteine and acetylcarnitine on mitochondrial respiration. Folia Biol. 2016;62:53–66. doi: 10.14712/fb2016062020053. PubMed DOI

Fišar Z., Singh N., Hroudová J. Cannabinoid-induced changes in respiration of brain mitochondria. Toxicol. Lett. 2014;231:62–71. doi: 10.1016/j.toxlet.2014.09.002. PubMed DOI

Hroudová J., Fišar Z. In vitro inhibition of mitochondrial respiratory rate by antidepressants. Toxicol. Lett. 2012;213:345–352. doi: 10.1016/j.toxlet.2012.07.017. PubMed DOI

Singh N., Hroudová J., Fišar Z. In vitro effects of cognitives and nootropics on mitochondrial respiration and monoamine oxidase activity. Mol. Neurobiol. 2017;54:5894–5904. doi: 10.1007/s12035-016-0121-y. PubMed DOI

Rawat P., Sehar U., Bisht J., Selman A., Culberson J., Reddy P.H. Phosphorylated tau in Alzheimer’s disease and other tauopathies. Int. J. Mol. Sci. 2022;23:12841. doi: 10.3390/ijms232112841. PubMed DOI PMC

Pickett E.K., Rose J., McCrory C., McKenzie C.A., King D., Smith C., Gillingwater T.H., Henstridge C.M., Spires-Jones T.L. Region-specific depletion of synaptic mitochondria in the brains of patients with Alzheimer’s disease. Acta Neuropathol. 2018;136:747–757. doi: 10.1007/s00401-018-1903-2. PubMed DOI PMC

Manczak M., Reddy P.H. Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum. Mol. Genet. 2012;21:5131–5146. doi: 10.1093/hmg/dds360. PubMed DOI PMC

Di J., Cohen L.S., Corbo C.P., Phillips G.R., El Idrissi A., Alonso A.D. Abnormal tau induces cognitive impairment through two different mechanisms: Synaptic dysfunction and neuronal loss. Sci. Rep. 2016;6:20833. doi: 10.1038/srep20833. PubMed DOI PMC

Jack C.R., Jr., Bennett D.A., Blennow K., Carrillo M.C., Dunn B., Haeberlein S.B., Holtzman D.M., Jagust W., Jessen F., Karlawish J., et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 2018;14:535–562. doi: 10.1016/j.jalz.2018.02.018. PubMed DOI PMC

McKhann G.M., Knopman D.S., Chertkow H., Hyman B.T., Jack C.R., Jr., Kawas C.H., Klunk W.E., Koroshetz W.J., Manly J.J., Mayeux R., et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–269. doi: 10.1016/j.jalz.2011.03.005. PubMed DOI PMC

Cummings J., Zhou Y., Lee G., Zhong K., Fonseca J., Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2023;9:e12385. doi: 10.1002/trc2.12385. PubMed DOI PMC

Reddy A.P., Reddy P.H. Mitochondria-targeted molecules as potential drugs to treat patients with Alzheimer’s disease. Prog. Mol. Biol. Transl. Sci. 2017;146:173–201. doi: 10.1016/bs.pmbts.2016.12.010. PubMed DOI

Mashal Y., Abdelhady H., Iyer A.K. Comparison of tau and amyloid-β targeted immunotherapy nanoparticles for Alzheimer’s disease. Biomolecules. 2022;12:1001. doi: 10.3390/biom12071001. PubMed DOI PMC

Tolar M., Hey J., Power A., Abushakra S. Neurotoxic soluble amyloid oligomers drive Alzheimer’s pathogenesis and represent a clinically validated target for slowing disease progression. Int. J. Mol. Sci. 2021;22:6355. doi: 10.3390/ijms22126355. PubMed DOI PMC

Aillaud I., Funke S.A. Tau aggregation inhibiting peptides as potential therapeutics for Alzheimer disease. Cell Mol. Neurobiol. 2023;43:951–961. doi: 10.1007/s10571-022-01230-7. PubMed DOI PMC

Fišar Z., Hroudová J. CoQ10 and mitochondrial dysfunction in Alzheimer’s disease. Antioxidants. 2024;13:191. doi: 10.3390/antiox13020191. PubMed DOI PMC

Wang L., Bharti, Kumar R., Pavlov P.F., Winblad B. Small molecule therapeutics for tauopathy in Alzheimer’s disease: Walking on the path of most resistance. Eur. J. Med. Chem. 2021;209:112915. doi: 10.1016/j.ejmech.2020.112915. PubMed DOI

Ghazanfari D., Noori M.S., Bergmeier S.C., Hines J.V., McCall K.D., Goetz D.J. A novel GSK-3 inhibitor binds to GSK-3β via a reversible, time and Cys-199-dependent mechanism. Bioorg Med. Chem. 2021;40:116179. doi: 10.1016/j.bmc.2021.116179. PubMed DOI PMC

Medina M. An Overview on the clinical development of tau-based therapeutics. Int. J. Mol. Sci. 2018;19:1160. doi: 10.3390/ijms19041160. PubMed DOI PMC

Soeda Y., Takashima A. New insights into drug discovery targeting tau protein. Front. Mol. Neurosci. 2020;13:590896. doi: 10.3389/fnmol.2020.590896. PubMed DOI PMC

Tolar M., Abushakra S., Sabbagh M. The path forward in Alzheimer’s disease therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimers Dement. 2020;16:1553–1560. doi: 10.1016/j.jalz.2019.09.075. PubMed DOI

Mamsa S.S.A., Meloni B.P. Arginine and arginine-rich peptides as modulators of protein aggregation and cytotoxicity associated with Alzheimer’s disease. Front. Mol. Neurosci. 2021;14:759729. doi: 10.3389/fnmol.2021.759729. PubMed DOI PMC

Andreux P.A., Houtkooper R.H., Auwerx J. Pharmacological approaches to restore mitochondrial function. Nat. Rev. Drug Discov. 2013;12:465–483. doi: 10.1038/nrd4023. PubMed DOI PMC

Hroudová J., Singh N., Fišar Z., Ghosh K.K. Progress in drug development for Alzheimer’s disease: An overview in relation to mitochondrial energy metabolism. Eur. J. Med. Chem. 2016;121:774–784. doi: 10.1016/j.ejmech.2016.03.084. PubMed DOI

Weissig V. Drug development for the therapy of mitochondrial diseases. Trends Mol. Med. 2020;26:40–57. doi: 10.1016/j.molmed.2019.09.002. PubMed DOI