REFERENCES
2. Wang QH, Wang X, Bu XL, et al. Comorbidity burden of dementia: a hospital-based retrospective study from 2003 to 2012 in seven cities in China. Neurosci Bull 2017;33:703-10.
4. Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci 2020;23:1183-93.
5. Hernandez P, Lee G, Sjoberg M, Maccioni RB. Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25-35): involvement of lipid rafts. J Alzheimers Dis 2009;16:149-56.
6. Terwel D, Muyllaert D, Dewachter I, et al. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol 2008;172:786-98.
7. Gamblin TC, Chen F, Zambrano A, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 2003;100:10032-7.
8. Peters F, Salihoglu H, Pratsch K, et al. Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer’s disease. EMBO J 2019;38:e102345.
9. Pascoal TA, Mathotaarachchi S, Mohades S, et al. Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol Psychiatry 2017;22:306-11.
10. Fortea J, Vilaplana E, Alcolea D, et al. Alzheimer’s disease neuroimaging initiative. Cerebrospinal fluid β-amyloid and phospho-tau biomarker interactions affecting brain structure in preclinical Alzheimer disease. Ann Neurol 2014;76:223-30.
11. Timmers M, Tesseur I, Bogert J, et al. Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer’s disease. Neurobiol Aging 2019;79:131-41.
12. Kabir MT, Uddin MS, Mamun AA, et al. Combination drug therapy for the management of Alzheimer’s disease. Int J Mol Sci 2020;21:3272.
14. Hampel H, Vassar R, De Strooper B, et al. The β-Secretase BACE1 in Alzheimer’s disease. Biol Psychiatry 2021;89:745-56.
15. Penninkilampi R, Brothers HM, Eslick GD. Pharmacological agents targeting γ-secretase increase risk of cancer and cognitive decline in Alzheimer’s disease patients: a systematic review and meta-analysis. J Alzheimers Dis 2016;53:1395-404.
16. Wolfe MS. Probing mechanisms and therapeutic potential of γ-Secretase in Alzheimer’s disease. Molecules 2021;26:388.
17. Sagnou M, Mavroidi B, Kaminari A, Boukos N, Pelecanou M. Novel isatin thiosemicarbazone derivatives as potent inhibitors of β-Amyloid peptide aggregation and toxicity. ACS Chem Neurosci 2020;11:2266-76.
18. Sterner RM, Takahashi PY, Yu Ballard AC. Active vaccines for Alzheimer disease treatment. J Am Med Dir Assoc 2016;17:862.e11-5.
19. Gilman S, Koller M, Black RS, et al. AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-62.
20. La Joie R, Visani AV, Baker SL, et al. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med 2020;12:eaau5732.
21. Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and Tau hypothesis in Alzheimer’s disease. Front Neurosci 2018;12:25.
22. Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 2015;21:394-402.
24. Tapia-Rojas C, Cabezas-Opazo F, Deaton CA, Vergara EH, Johnson GVW, Quintanilla RA. It’s all about tau. Prog Neurobiol 2019;175:54-76.
25. Ait-Bouziad N, Chiki A, Limorenko G, Xiao S, Eliezer D, Lashuel HA. Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau. J Biol Chem 2020;295:7905-22.
26. Braak H, Braak E. Staging of alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 1995;16:271-8.
27. Clavaguera F, Duyckaerts C, Haïk S. Prion-like properties of Tau assemblies. Curr Opin Neurobiol 2020;61:49-57.
28. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 2016;15:673-84.
29. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;112:389-404.
30. Alquezar C, Arya S, Kao AW. Tau post-translational modifications: dynamic transformers of Tau function, degradation, and aggregation. Front Neurol 2020;11:595532.
31. Köpke E, Tung YC, Shaikh S, et al. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 1993;268:24374-84.
32. Noble W, Hanger DP, Miller CC, Lovestone S. The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 2013;4:83.
33. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 2001;98:6923-8.
34. Caballero B, Bourdenx M, Luengo E, et al. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nat Commun 2021;12:2238.
35. Min SW, Cho SH, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010;67:953-66.
36. Cohen TJ, Guo JL, Hurtado DE, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2011;2:252.
37. Wang JZ, Grundke-Iqbal I, Iqbal K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat Med 1996;2:871-5.
38. Reynolds MR, Berry RW, Binder LI. Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer’s disease. Biochemistry 2005;44:1690-700.
39. Cotman CW, Poon WW, Rissman RA, Blurton-Jones M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J Neuropathol Exp Neurol 2005;64:104-12.
40. Zhao X, Kotilinek LA, Smith B, et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat Med 2016;22:1268-76.
41. Berry RW, Abraha A, Lagalwar S, et al. Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment. Biochemistry 2003;42:8325-31.
42. Pérez MJ, Vergara-Pulgar K, Jara C, Cabezas-Opazo F, Quintanilla RA. Caspase-cleaved Tau impairs mitochondrial dynamics in Alzheimer’s disease. Mol Neurobiol 2018;55:1004-18.
43. Lee MJ, Lee JH, Rubinsztein DC. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog Neurobiol 2013;105:49-59.
44. Funk KE, Thomas SN, Schafer KN, et al. Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity. Biochem J 2014;462:77-88.
45. Maina MB, Al-Hilaly YK, Oakley S, et al. Dityrosine cross-links are present in Alzheimer’s disease-derived tau oligomers and paired helical filaments (PHF) which promotes the stability of the PHF-core tau (297-391). bioRxiv 2022; doi: 10.1101/2022.05.28.493839.
46. Maina MB, Al-Hilaly YK, Burra G, et al. Oxidative stress conditions result in trapping of PHF-core Tau (297-391) intermediates. Cells 2021;10:703.
47. Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R. Preparation and characterization of neurotoxic tau oligomers. Biochemistry 2010;49:10039-41.
48. Qian W, Shi J, Yin X, et al. PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis 2010;19:1221-9.
49. Nicolia V, Fuso A, Cavallaro RA, Di Luzio A, Scarpa S. B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A. J Alzheimers Dis 2010;19:895-907.
50. Lauretti E, Dincer O, Praticò D. Glycogen synthase kinase-3 signaling in Alzheimer’s disease. Biochim Biophys Acta Mol Cell Res 2020;1867:118664.
51. Serenó L, Coma M, Rodríguez M, et al. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis 2009;35:359-67.
52. Wang H, Huang S, Yan K, et al. Tideglusib, a chemical inhibitor of GSK3β, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim Biophys Acta 2016;1860:2076-85.
53. Morales-Garcia JA, Luna-Medina R, Alonso-Gil S, et al. Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo. ACS Chem Neurosci 2012;3:963-71.
54. Lovestone S, Boada M, Dubois B, et al. ARGO investigators. A phase II trial of tideglusib in Alzheimer’s disease. J Alzheimers Dis 2015;45:75-88.
55. Matsunaga S, Fujishiro H, Takechi H. Efficacy and safety of glycogen synthase kinase 3 inhibitors for Alzheimer’s disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis 2019;69:1031-9.
56. Hampel H, Lista S, Mango D, et al. Alzheimer Precision Medicine Initiative (APMI). Lithium as a treatment for Alzheimer’s disease: the systems pharmacology perspective. J Alzheimers Dis 2019;69:615-29.
57. Smith KA, Cipriani A. Lithium and suicide in mood disorders: updated meta-review of the scientific literature. Bipolar Disord 2017;19:575-86.
58. Hampel H, Ewers M, Bürger K, et al. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009;70:922-31.
59. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011;198:351-6.
60. Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry 2019;215:668-74.
61. Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res 2013;10:104-7.
62. Damri O, Shemesh N, Agam G. Is there justification to treat neurodegenerative disorders by repurposing drugs? Int J Mol Sci 2020;22:189.
63. Morris G, Berk M. The putative use of lithium in Alzheimer’s disease. Curr Alzheimer Res 2016;13:853-61.
64. Gildengers A, Aizenstein H, Anderson S, et al. Lithium as a treatment to prevent impairment of cognition in elders(LATTICE)2017;Available from: https://clinicaltrials.gov/ct2/show/NCT03185208 [Last accessed on 20 Jul 2022].
65. Georgievska B, Sandin J, Doherty J, et al. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J Neurochem 2013;125:446-56.
66. Hu S, Hu M, Liu J, et al. Phosphorylation of Tau and α-synuclein induced neurodegeneration in MPTP mouse model of Parkinson’s disease. Neuropsychiatr Dis Treat 2020;16:651-63.
67. Cruz JC, Tseng H, Goldman JA, Shih H, Tsai L. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 2003;40:471-83.
68. Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 2016;12:15-27.
69. Piedrahita D, Hernández I, López-Tobón A, et al. Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer’s mice. J Neurosci 2010;30:13966-76.
70. Zhao Y, Wang C, He W, Cai Z. Ameliorating Alzheimer’s-like pathology by Minocycline via inhibiting Cdk5/p25 signaling. Curr Neuropharmacol 2021; doi: 10.2174/1570159X19666211202124925.
71. Li T, Hawkes C, Qureshi HY, Kar S, Paudel HK. Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau site-specifically for glycogen synthase kinase 3beta. Biochemistry 2006;45:3134-45.
72. Engmann O, Giese KP. Crosstalk between Cdk5 and GSK3beta: implications for Alzheimer’s disease. Front Mol Neurosci 2009;2:2.
73. Wen Y, Planel E, Herman M, et al. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci 2008;28:2624-32.
74. Wang HH, Li Y, Li A, et al. Forskolin induces hyperphosphorylation of Tau accompanied by cell cycle reactivation in primary hippocampal neurons. Mol Neurobiol 2018;55:696-706.
75. Villa V, Montalto G, Caudano F, Fedele E, Ricciarelli R. Selective inhibition of phosphodiesterase 4D increases tau phosphorylation at Ser214 residue. Biofactors 2022; doi: 10.1002/biof.1847.
76. Zheng-Fischhöfer Q, Biernat J, Mandelkow EM, Illenberger S, Godemann R, Mandelkow E. Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur J Biochem 1998;252:542-52.
77. Domise M, Didier S, Marinangeli C, et al. AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo. Sci Rep 2016;6:26758.
78. Vingtdeux V, Davies P, Dickson DW, Marambaud P. AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies. Acta Neuropathol 2011;121:337-49.
79. Wang L, Li N, Shi FX, et al. Upregulation of AMPK ameliorates Alzheimer’s disease-like Tau pathology and memory impairment. Mol Neurobiol 2020;57:3349-61.
80. Zhang S, Wang C, Lu J, et al. In-cell NMR study of Tau and MARK2 phosphorylated Tau. Int J Mol Sci 2018;20:90.
81. Wu PR, Tsai PI, Chen GC, et al. DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity. Cell Death Differ 2011;18:1507-20.
82. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 2005;22:1942-50.
83. Virshup DM, Shenolikar S. From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 2009;33:537-45.
84. Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 2007;25:59-68.
85. van Eersel J, Ke YD, Liu X, et al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proc Natl Acad Sci U S A 2010;107:13888-93.
86. Malpas CB, Vivash L, Genc S, et al. A phase IIa randomized control trial of VEL015 (Sodium Selenate) in mild-moderate Alzheimer’s disease. J Alzheimers Dis 2016;54:223-32.
87. Vivash L, Malpas CB, Hovens CM, et al. Sodium selenate as a disease-modifying treatment for mild-moderate Alzheimer’s disease: an open-label extension study. BMJ Neurol Open 2021;3:e000223.
88. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm (Vienna) 2005;112:813-38.
89. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U S A 2004;101:10804-9.
90. Graham DL, Gray AJ, Joyce JA, et al. Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy. Neuropharmacology 2014;79:307-13.
91. Hastings NB, Wang X, Song L, et al. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener 2017;12:39.
92. Yuzwa SA, Shan X, Macauley MS, et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol 2012;8:393-9.
93. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis 2006;9:1-12.
94. Zhu Y, Shan X, Yuzwa SA, Vocadlo DJ. The emerging link between O-GlcNAc and Alzheimer disease. J Biol Chem 2014;289:34472-81.
95. Paul S, Haskali MB, Liow JS, et al. Evaluation of a PET radioligand to image O-GlcNAcase in brain and periphery of rhesus monkey and knock-out mouse. J Nucl Med 2019;60:129-34.
96. Shin MK, Vázquez-Rosa E, Koh Y, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell 2021;184:2715-2732.e23.
97. Min SW, Chen X, Tracy TE, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 2015;21:1154-62.
98. VandeVrede L, Dale ML, Fields S, et al. Open-label phase 1 futility studies of salsalate and young plasma in progressive supranuclear palsy. Mov Disord Clin Pract 2020;7:440-7.
99. Gu J, Xu W, Jin N, et al. Truncation of Tau selectively facilitates its pathological activities. J Biol Chem 2020;295:13812-28.
100. Šimić G, Babić Leko M, Wray S, et al. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 2016;6:6.
101. Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013;80:402-14.
102. Yanamandra K, Jiang H, Mahan TE, et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol 2015;2:278-88.
103. Corsetti V, Borreca A, Latina V, et al. Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer’s disease models. Brain Commun 2020;2:fcaa039.
104. Singh G, Liu P, Yao KR, et al. Caspase-2 inhibitor blocks Tau truncation and restores excitatory neurotransmission in neurons modeling FTDP-17 tauopathy. ACS Chem Neurosci 2022;13:1549-57.
105. Brier MR, Gordon B, Friedrichsen K, et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 2016;8:338ra66.
106. Penke B, Szűcs M, Bogár F. Oligomerization and conformational change turn monomeric β-Amyloid and Tau proteins toxic: their role in Alzheimer’s pathogenesis. Molecules 2020;25:1659.
107. Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A 1996;93:11213-8.
108. Riha PD, Rojas JC, Gonzalez-Lima F. Beneficial network effects of methylene blue in an amnestic model. Neuroimage 2011;54:2623-34.
109. Wischik CM, Staff RT, Wischik DJ, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis 2015;44:705-20.
110. Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. The Lancet 2016;388:2873-84.
111. Baddeley TC, McCaffrey J, Storey JM, et al. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J Pharmacol Exp Ther 2015;352:110-8.
112. Wilcock GK, Gauthier S, Frisoni GB, et al. Potential of low dose leuco-methylthioninium bis(Hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary outcome in a phase III clinical trial. J Alzheimers Dis 2018;61:435-57.
113. Kroth H, Ansaloni A, Varisco Y, et al. Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation. J Biol Chem 2012;287:34786-800.
114. Poli S. SMALL MOLECULES TARGETING TAU PROPAGATION DEMONSTRATE EFFICACY IN AN AGGRESSIVE TAUOPATHY MOUSE MODE. Available from: https://www.acimmune.com/ [Last accessed on 20 Jul 2022].
115. Frautschy SA, Cole GM. Why pleiotropic interventions are needed for Alzheimer’s disease. Mol Neurobiol 2010;41:392-409.
116. Chen M, Du ZY, Zheng X, Li DL, Zhou RP, Zhang K. Use of curcumin in diagnosis, prevention, and treatment of Alzheimer’s disease. Neural Regen Res 2018;13:742-52.
117. Ege D. Action mechanisms of curcumin in Alzheimer’s disease and its brain targeted delivery. Materials (Basel) 2021;14:3332.
118. Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimers Res Ther 2013;5:25.
119. Viswanathan GK, Shwartz D, Losev Y, et al. Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model. Cell Mol Life Sci 2020;77:2795-813.
120. Shin SJ, Park YH, Jeon SG, et al. Red ginseng inhibits Tau aggregation and promotes Tau dissociation in vitro. Oxid Med Cell Longev 2020;2020:7829842.
121. Thapa A, Jett SD, Chi EY. Curcumin attenuates amyloid-β aggregate toxicity and modulates amyloid-β aggregation pathway. ACS Chem Neurosci 2016;7:56-68.
122. Ramesh M, Acharya A, Murugan NA, Ila H, Govindaraju T. Thiophene-based dual modulators of Aβ and Tau aggregation. Chembiochem 2021;22:3348-57.
123. Son SH, Do JM, Yoo JN, et al. Identification of ortho catechol-containing isoflavone as a privileged scaffold that directly prevents the aggregation of both amyloid β plaques and tau-mediated neurofibrillary tangles and its in vivo evaluation. Bioorg Chem 2021;113:105022.
124. DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 2017;9:eaag0481.
125. DeVos SL, Goncharoff DK, Chen G, et al. Antisense reduction of tau in adult mice protects against seizures. J Neurosci 2013;33:12887-97.
126. Biswas S, Kalil K. The microtubule-associated protein Tau mediates the organization of microtubules and their dynamic exploration of actin-rich lamellipodia and filopodia of cortical growth cones. J Neurosci 2018;38:291-307.
127. Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 2001;114:1179-87.
128. Yu W, Qiang L, Solowska JM, Karabay A, Korulu S, Baas PW. The microtubule-severing proteins spastin and katanin participate differently in the formation of axonal branches. Mol Biol Cell 2008;19:1485-98.
129. Velazquez R, Ferreira E, Tran A, et al. Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits. Aging Cell 2018;17:e12775.
130. Sapir T, Frotscher M, Levy T, Mandelkow EM, Reiner O. Tau’s role in the developing brain: implications for intellectual disability. Hum Mol Genet 2012;21:1681-92.
131. Violet M, Delattre L, Tardivel M, et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci 2014;8:84.
132. Ikegami S. Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett 2000;279:129-32.
133. Barbier P, Zejneli O, Martinho M, et al. Role of Tau as a microtubule-associated protein: structural and functional aspects. Front Aging Neurosci 2019;11:204.
134. Paonessa F, Evans LD, Solanki R, et al. Microtubules deform the nuclear membrane and disrupt nucleocytoplasmic transport in Tau-mediated frontotemporal dementia. Cell Rep 2019;26:582-593.e5.
135. Ivashko-Pachima Y, Sayas CL, Malishkevich A, Gozes I. ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy. Mol Psychiatry 2017;22:1335-44.
136. Varidaki A, Hong Y, Coffey ET. Repositioning microtubule stabilizing drugs for brain disorders. Front Cell Neurosci 2018;12:226.
137. Vulih-Shultzman I, Pinhasov A, Mandel S, et al. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther 2007;323:438-49.
138. Matsuoka Y, Jouroukhin Y, Gray AJ, et al. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 2008;325:146-53.
139. Merenlender-Wagner A, Pikman R, Giladi E, Andrieux A, Gozes I. NAP (davunetide) enhances cognitive behavior in the STOP heterozygous mouse--a microtubule-deficient model of schizophrenia. Peptides 2010;31:1368-73.
140. Morimoto BH, Schmechel D, Hirman J, Blackwell A, Keith J, Gold M. AL-108-211 Study. A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Dement Geriatr Cogn Disord 2013;35:325-36.
141. Barten DM, Fanara P, Andorfer C, et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J Neurosci 2012;32:7137-45.
142. Brunden KR, Zhang B, Carroll J, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci 2010;30:13861-6.
143. Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009;11:909-13.
144. Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 2015;129:221-37.
145. Gibbons GS, Lee VMY, Trojanowski JQ. Mechanisms of cell-to-cell transmission of pathological Tau: a review. JAMA Neurol 2019;76:101-8.
146. Wang Y, Balaji V, Kaniyappan S, et al. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener 2017;12:5.
147. Pérez M, Avila J, Hernández F. Propagation of Tau via extracellular vesicles. Front Neurosci 2019;13:698.
150. Kuang H, Tan CY, Tian HZ, et al. Exploring the bi-directional relationship between autophagy and Alzheimer’s disease. CNS Neurosci Ther 2020;26:155-66.
151. Meco A, Li JG, Blass BE, Abou-Gharbia M, Lauretti E, Praticò D. 12/15-lipoxygenase inhibition reverses cognitive impairment, brain amyloidosis, and Tau pathology by stimulating autophagy in aged triple transgenic mice. Biol Psychiatry 2017;81:92-100.
152. Silva MC, Nandi GA, Tentarelli S, et al. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons. Nat Commun 2020;11:3258.
153. Zhang ZH, Wu QY, Zheng R, et al. Selenomethionine mitigates cognitive decline by targeting both Tau hyperphosphorylation and autophagic clearance in an Alzheimer’s disease mouse model. J Neurosci 2017;37:2449-62.
154. Tang M, Ji C, Pallo S, Rahman I, Johnson GVW. Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner. Neurobiol Aging 2018;63:128-39.
155. Smith PY, Hernandez-Rapp J, Jolivette F, et al. miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo. Hum Mol Genet 2015;24:6721-35.
156. Shibuya Y, Niu Z, Bryleva EY, et al. Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol Aging 2015;36:2248-59.
157. Sun H, Zhong Y, Zhu X, et al. A tauopathy-homing and autophagy-activating nanoassembly for specific clearance of pathogenic Tau in Alzheimer’s disease. ACS Nano 2021;15:5263-75.
158. Tung YT, Wang BJ, Hu MK, et al. Autophagy: a double-edged sword in Alzheimer’s disease. J Biosci 2012;37:157-65.
159. Sandusky-Beltran LA, Sigurdsson EM. Tau immunotherapies: Lessons learned, current status and future considerations. Neuropharmacology 2020;175:108104.
160. Bittar A, Bhatt N, Kayed R. Advances and considerations in AD tau-targeted immunotherapy. Neurobiol Dis 2020;134:104707.
161. Rosenmann H, Grigoriadis N, Karussis D, et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch Neurol 2006;63:1459-67.
162. Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 2014;6:44.
163. Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol 2017;16:123-34.
164. Novak P, Schmidt R, Kontsekova E, et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimers Res Ther 2018;10:108.
165. Novak P, Zilka N, Zilkova M, et al. AADvac1, an active immunotherapy for Alzheimer’s disease and non Alzheimer tauopathies: an overview of preclinical and clinical development. J Prev Alzheimers Dis 2019;6:63-9.
166. Novak P, Kovacech B, Katina S, et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat Aging 2021;1:521-34.
167. Theunis C, Crespo-Biel N, Gafner V, et al. Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS One 2013;8:e72301.
168. Rozenstein-Tsalkovich L, Grigoriadis N, Lourbopoulos A, et al. Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation. Exp Neurol 2013;248:451-6.
169. Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem 2011;118:658-67.
170. Dai CL, Chen X, Kazim SF, et al. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J Neural Transm (Vienna) 2015;122:607-17.
171. Buée L, Bussière T, Buée-scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000;33:95-130.
172. Collin L, Bohrmann B, Göpfert U, Oroszlan-Szovik K, Ozmen L, Grüninger F. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 2014;137:2834-46.
173. Troquier L, Caillierez R, Burnouf S, et al. Targeting phospho-Ser422 by active Tau Immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr Alzheimer Res 2012;9:397-405.
174. Sopko R, Golonzhka O, Arndt J, et al. Characterization of tau binding by gosuranemab. Neurobiol Dis 2020;146:105120.
175. Boxer AL, Qureshi I, Ahlijanian M, et al. Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial. Lancet Neurol 2019;18:549-58.
176. Bright J, Hussain S, Dang V, et al. Human secreted tau increases amyloid-beta production. Neurobiol Aging 2015;36:693-709.
177. Folch J, Petrov D, Ettcheto M, et al. Current research therapeutic strategies for Alzheimer’s disease treatment. Neural Plast 2016;2016:8501693.
178. Yanamandra K, Patel TK, Jiang H, et al. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci Transl Med 2017;9:eaal2029.
179. Qureshi IA, Tirucherai G, Ahlijanian MK, Kolaitis G, Bechtold C, Grundman M. A randomized, single ascending dose study of intravenous BIIB092 in healthy participants. Alzheimers Dement (N Y) 2018;4:746-55.
180. Lee SH, Le Pichon CE, Adolfsson O, et al. Antibody-mediated targeting of Tau In vivo does not require effector function and microglial engagement. Cell Rep 2016;16:1690-700.
181. .
182. Chai X, Wu S, Murray TK, et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem 2011;286:34457-67.
183. Jicha GA, Bowser R, Kazam IG, Davies P. Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 1997;48:128-32.
184. 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.
185. Vitale F, Giliberto L, Ruiz S, Steslow K, Marambaud P, d’Abramo C. Anti-tau conformational scFv MC1 antibody efficiently reduces pathological tau species in adult JNPL3 mice. Acta Neuropathol Commun 2018;6:82.
186. Sigurdsson EM. Tau immunotherapies for Alzheimer’s disease and related tauopathies: progress and potential pitfalls. J Alzheimers Dis 2018;64:S555-65.
187. Galpern WR, Mercken M, Van Kolen K, et al. P1-052: a single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-phospho-tau antibody jnj-63733657 in healthy subjects. Alzheimers Dement 2019;15:P252-3.
188. A study to investigate safety and tolerability, pharmacokinetics and pharmacodynamics of JNJ-63733657 in healthy subjects and subjects with Alzheimer’s disease. Available from: https://clinicaltrials.gov [Last accessed on 20 Jul 2022].
189. Albert M, Mairet-Coello G, Danis C, et al. Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. Brain 2019;142:1736-50.
190. Courade JP, Angers R, Mairet-Coello G, et al. Epitope determines efficacy of therapeutic anti-Tau antibodies in a functional assay with human Alzheimer Tau. Acta Neuropathol 2018;136:729-45.
191. Kondo A, Shahpasand K, Mannix R, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 2015;523:431-6.
192. Albayram O, Kondo A, Mannix R, et al. Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nat Commun 2017;8:1000.
193. Mohsenian Sisakht A, Karamzade-Ziarati N, Jahanbakhshi A, et al. Pathogenic cis p-tau levels in CSF reflects severity of traumatic brain injury. Neurol Res 2022;44:496-502.
194. Qiu C, Albayram O, Kondo A, et al. Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice. Sci Transl Med 2021;13:eaaz7615.
195. Nobuhara CK, DeVos SL, Commins C, et al. Tau antibody targeting pathological species blocks neuronal uptake and interneuron propagation of Tau in vitro. Am J Pathol 2017;187:1399-412.
196. Czerkowicz J, Chen W, Wang Q, et al. PAN-TAU ANTIBODY BIIB076 EXHIBITS PROMISING SAFETY AND BIOMARKER PROFILE IN CYNOMOLGUS MONKEY TOXICITY STUDY. Alzheimers Dement 2017;13:P1271.
197. Funk KE, Mirbaha H, Jiang H, Holtzman DM, Diamond MI. Distinct therapeutic mechanisms of Tau antibodies: promoting microglial clearance versus blocking neuronal uptake. J Biol Chem 2015;290:21652-62.
198. Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular propagation of Tau aggregation by fibrillar species. J Biol Chem 2012;287:19440-51.
199. West T, Hu Y, Verghese PB, et al. Preclinical and clinical development of ABBV-8E12, a humanized anti-Tau antibody, for treatment of Alzheimer’s disease and other tauopathies. J Prev Alzheimers Dis 2017;4:236-41.
200. Höglinger GU, Litvan I, Mendonca N, et al. Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial. Lancet Neurol 2021;20:182-92.
201. Roberts M, Sevastou I, Imaizumi Y, et al. Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer’s disease. Acta Neuropathol Commun 2020;8:13.
202. Rosenqvist N, Asuni AA, Andersson CR, et al. Highly specific and selective anti-pS396-tau antibody C10.2 targets seeding-competent tau. Alzheimers Dement (N Y) 2018;4:521-34.
203. Andersson CR, Falsig J, Stavenhagen JB, et al. Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes. Sci Rep 2019;9:4658.
204. Gao C, Chu X, Gong W, et al. Neuron tau-targeting biomimetic nanoparticles for curcumin delivery to delay progression of Alzheimer’s disease. J Nanobiotechnology 2020;18:71.
205. Yang Z, Liu ZW, Allaker RP, et al. A review of nanoparticle functionality and toxicity on the central nervous system. J R Soc Interface 2010;7 Suppl 4:S411-22.
206. Nguyen TT, Dung Nguyen TT, Vo TK, et al. Nanotechnology-based drug delivery for central nervous system disorders. Biomed Pharmacother 2021;143:112117.
207. Ghalandari B, Asadollahi K, Shakerizadeh A, et al. Microtubule network as a potential candidate for targeting by gold nanoparticle-assisted photothermal therapy. J Photochem Photobiol B 2019;192:131-40.
208. Sonawane SK, Ahmad A, Chinnathambi S. Protein-capped metal nanoparticles inhibit Tau aggregation in Alzheimer’s disease. ACS Omega 2019;4:12833-40.
209. Bajracharya R, Caruso AC, Vella LJ, Nisbet RM. Current and emerging strategies for enhancing antibody delivery to the brain. Pharmaceutics 2021;13:2014.
210. Wolfram J, Zhu M, Yang Y, et al. Safety of nanoparticles in medicine. Curr Drug Targets 2015;16:1671-81.
211. Liang Y, Duan L, Lu J, Xia J. Engineering exosomes for targeted drug delivery. Theranostics 2021;11:3183-95.
212. Qi Y, Guo L, Jiang Y, Shi Y, Sui H, Zhao L. Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles. Drug Deliv 2020;27:745-55.
213. Congdon EE, Chukwu JE, Shamir DB, et al. Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy. EBioMedicine 2019;42:157-73.
214. Congdon EE, Lin Y, Rajamohamedsait HB, et al. Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy. Mol Neurodegener 2016;11:62.
215. Shamir DB, Deng Y, Wu Q, Modak S, Congdon EE, Sigurdsson EM. Dynamics of internalization and intracellular interaction of Tau antibodies and human pathological Tau protein in a human neuron-like model. Front Neurol 2020;11:602292.
216. Gu J, Congdon EE, Sigurdsson EM. Two novel Tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce Tau protein pathology. J Biol Chem 2013;288:33081-95.
217. Castillo-Carranza DL, Sengupta U, Guerrero-Muñoz MJ, et al. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci 2014;34:4260-72.
218. Congdon EE, Gu J, Sait HB, Sigurdsson EM. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J Biol Chem 2013;288:35452-65.
219. Tashima T. Delivery of intravenously administered antibodies targeting Alzheimer’s disease-relevant Tau species into the brain based on receptor-mediated transcytosis. Pharmaceutics 2022;14:411.
220. McEwan WA, Falcon B, Vaysburd M, et al. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc Natl Acad Sci U S A 2017;114:574-9.
221. Bergen M, Barghorn S, Biernat J, Mandelkow EM, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochim Biophys Acta 2005;1739:158-66.
222. Rai SK, Savastano A, Singh P, Mukhopadhyay S, Zweckstetter M. Liquid-liquid phase separation of tau: from molecular biophysics to physiology and disease. Protein Sci 2021;30:1294-314.
223. Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat Commun 2017;8:275.
224. Strittmatter WJ, Saunders AM, Goedert M, et al. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A 1994;91:11183-6.
225. Wang C, Xiong M, Gratuze M, et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 2021;109:1657-1674.e7.
226. Shi Y, Manis M, Long J, et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med 2019;216:2546-61.
