Abstract
Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.
Key points
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Therapies for Alzheimer disease in clinical trials are gradually shifting from amyloid-β (Aβ)-targeting to tau-targeting approaches.
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Early anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy.
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Most of the tau-targeting approaches that are currently in clinical trials are immunotherapies.
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Tau is likely to be a better target than Aβ once cognitive deficits manifest because the tau burden correlates better with clinical impairments than does the Aβ burden.
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Eventually, with continued improvements in diagnostics, both Aβ and tau are likely to be targeted prophylactically for clearance.
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References
Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 12, 459–509 (2016).
Dixit, R., Ross, J. L., Goldman, Y. E. & Holzbaur, E. L. Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089 (2008).
Vershinin, M., Carter, B. C., Razafsky, D. S., King, S. J. & Gross, S. P. Multiple-motor based transport and its regulation by Tau. Proc. Natl Acad. Sci. USA 104, 87–92 (2007).
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. 112, 389–404 (2006).
Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).
Wharton, S. B. et al. Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study. Acta Neuropathol. Commun. 4, 11 (2016).
Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913–4917 (1986).
Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010).
Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat. Med. 2, 871–875 (1996).
Mena, R., Edwards, P. C., Harrington, C. R., Mukaetova-Ladinska, E. B. & Wischik, C. M. Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer’s disease. Acta Neuropathol. 91, 633–641 (1996).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).
Murray, M. E. et al. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 10, 785–796 (2011).
Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).
Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089 (1986).
Kidd, M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197, 192–193 (1963).
Meraz-Rios, M. A., Lira-De Leon, K. I., Campos-Pena, V., De Anda-Hernandez, M. A. & Mena-Lopez, R. Tau oligomers and aggregation in Alzheimer’s disease. J. Neurochem. 112, 1353–1367 (2010).
Arima, K. Ultrastructural characteristics of tau filaments in tauopathies: immuno-electron microscopic demonstration of tau filaments in tauopathies. Neuropathology 26, 475–483 (2006).
Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526 (1989).
Himmler, A., Drechsel, D., Kirschner, M. W. & Martin, D. W. Jr. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol. Cell. Biol. 9, 1381–1388 (1989).
Noble, W., Hanger, D. P., Miller, C. C. & Lovestone, S. The importance of tau phosphorylation for neurodegenerative diseases. Front. Neurol. 4, 83 (2013).
Lindwall, G. & Cole, R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301–5305 (1984).
Luna-Muñoz, J., Chávez-Macías, L., García-Sierra, F. & Mena, R. Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J. Alzheimers Dis. 12, 365–375 (2007).
Augustinack, J. C., Schneider, A., Mandelkow, E. M. & Hyman, B. T. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol. 103, 26–35 (2002).
Hanger, D. P. & Wray, S. Tau cleavage and tau aggregation in neurodegenerative disease. Biochem. Soc. Trans. 38, 1016–1020 (2010).
Kimura, T. et al. Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments. Dementia 7, 177–181 (1996).
Yoshida, H. & Goedert, M. Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38δ or JNK2 in the presence of heparin generates the AT100 epitope. J. Neurochem. 99, 154–164 (2006).
Shukla, V., Skuntz, S. & Pant, H. C. Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Arch. Med. Res. 43, 655–662 (2012).
Tell, V. & Hilgeroth, A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front. Cell. Neurosci. 7, 189 (2013).
Yarza, R., Vela, S., Solas, M. & Ramirez, M. J. c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front. Pharmacol. 6, 321 (2015).
Liu, S. L. et al. The role of Cdk5 in Alzheimer’s disease. Mol. Neurobiol. 53, 4328–4342 (2016).
Wilkaniec, A., Czapski, G. A. & Adamczyk, A. Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. J. Neurochem. 136, 222–233 (2016).
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. 22, 1942–1950 (2005).
Sontag, J. M. & Sontag, E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front. Mol. Neurosci. 7, 16 (2014).
Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016).
Cotman, C. W., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 64, 104–112 (2005).
Guo, T., Noble, W. & Hanger, D. P. Roles of tau protein in health and disease. Acta Neuropathol. 133, 665–704 (2017).
Zhao, X. et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 22, 1268–1276 (2016).
Jadhav, S. et al. Truncated tau deregulates synaptic markers in rat model for human tauopathy. Front. Cell. Neurosci. 9, 24 (2015).
Liu, F. et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 132, 1820–1832 (2009).
Cash, A. D. et al. Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am. J. Pathol. 162, 1623–1627 (2003).
Hempen, B. & Brion, J. P. Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 55, 964–972 (1996).
Zhang, F. et al. Posttranslational modifications of α-tubulin in Alzheimer disease. Transl Neurodegener. 4, 9 (2015).
Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307, 1282–1288 (2005).
Stamer, K., Vogel, R., Thies, E., Mandelkow, E. & Mandelkow, E. M. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156, 1051–1063 (2002).
Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002).
Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. Science 330, 198 (2010).
Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).
Nelson, P. T. et al. Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J. Neuropathol. Exp. Neurol. 66, 1136–1146 (2007).
Vazquez, A. Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases. PLOS ONE 8, e63822 (2013).
Mandelkow, E. M., Stamer, K., Vogel, R., Thies, E. & Mandelkow, E. Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol. Aging 24, 1079–1085 (2003).
Callahan, L. M., Vaules, W. A. & Coleman, P. D. Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 58, 275–287 (1999).
Ginsberg, S. D., Hemby, S. E., Lee, V. M., Eberwine, J. H. & Trojanowski, J. Q. Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Ann. Neurol. 48, 77–87 (2000).
Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017).
Cárdenas-Aguayo Mdel, C., Gómez-Virgilio, L., DeRosa, S. & Meraz-Ríos, M. A. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem. Neurosci. 5, 1178–1191 (2014).
Fagan, A. M. et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci. Transl Med. 6, 226ra30 (2014).
Hall, S. et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch. Neurol. 69, 1445–1452 (2012).
Hu, W. T., Trojanowski, J. Q. & Shaw, L. M. Biomarkers in frontotemporal lobar degenerations — progress and challenges. Prog. Neurobiol. 95, 636–648 (2011).
Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016).
Wagshal, D. et al. Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and progressive supranuclear palsy. J. Neurol. Neurosurg. Psychiatry 86, 244–250 (2015).
Mufson, E. J., Ward, S. & Binder, L. Prefibrillar tau oligomers in mild cognitive impairment and Alzheimer’s disease. Neurodegener. Dis. 13, 151–153 (2014).
Flach, K. et al. Tau oligomers impair artificial membrane integrity and cellular viability. J. Biol. Chem. 287, 43223–43233 (2012).
Lasagna-Reeves, C. A. et al. The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol. Commun. 2, 56 (2014).
Goedert, M. & Spillantini, M. G. Propagation of Tau aggregates. Mol. Brain 10, 18 (2017).
Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015).
Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J. & Sargeant, T. J. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer’s disease? J. Neurochem. 140, 703–717 (2017).
Zare-Shahabadi, A., Masliah, E., Johnson, G. V. & Rezaei, N. Autophagy in Alzheimer’s disease. Rev. Neurosci. 26, 385–395 (2015).
Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).
Tramutola, A. et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J. Neurochem. 133, 739–749 (2015).
Li, X., Alafuzoff, I., Soininen, H., Winblad, B. & Pei, J. J. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J. 272, 4211–4220 (2005).
Lafay-Chebassier, C. et al. mTOR/p70S6k signalling alteration by Aβ exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer’s disease. J. Neurochem. 94, 215–225 (2005).
Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008).
Boland, B. et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J. Neurosci. 28, 6926–6937 (2008).
Sanchez-Varo, R. et al. Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus. Acta Neuropathol. 123, 53–70 (2012).
Bordi, M. et al. Autophagy flux in CA1 neurons of Alzheimer hippocampus: increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy 12, 2467–2483 (2016).
Piras, A., Collin, L., Gruninger, F., Graff, C. & Ronnback, A. Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. Commun. 4, 22 (2016).
Yu, W. H. et al. Macroautophagy — a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 171, 87–98 (2005).
Lin, C. L. et al. Amyloid-β suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity. Exp. Neurol. 275, 84–98 (2016).
Park, H. et al. Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. Hum. Mol. Genet. 21, 2725–2737 (2012).
Wang, Y. & Mandelkow, E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644–652 (2012).
Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235, 1641–1644 (1987).
Perry, G., Friedman, R., Shaw, G. & Chau, V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc. Natl Acad. Sci. USA 84, 3033–3036 (1987).
Gong, B., Radulovic, M., Figueiredo-Pereira, M. E. & Cardozo, C. The ubiquitin–proteasome system: potential therapeutic targets for Alzheimer’s disease and spinal cord injury. Front. Mol. Neurosci. 9, 4 (2016).
Morawe, T., Hiebel, C., Kern, A. & Behl, C. Protein homeostasis, aging and Alzheimer’s disease. Mol. Neurobiol. 46, 41–54 (2012).
Gurney, M. E., D’Amato, E. C. & Burgin, A. B. Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease. Neurotherapeutics 12, 49–56 (2015).
Sweeney, P. et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener. 6, 6 (2017).
Deger, J. M., Gerson, J. E. & Kayed, R. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell 14, 715–724 (2015).
Ittner, L. M. & Götz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer’s disease. Nat. Rev. Neurosci. 12, 65–72 (2011).
Ke, Y. D. et al. Lessons from tau-deficient mice. Int. J. Alzheimers Dis. 2012, 873270 (2012).
Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16, 543–552 (2015).
Zuckerman, J. E. & Davis, M. E. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat. Rev. Drug Discov. 14, 843–856 (2015).
Corey, D. R. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat. Neurosci. 20, 497–499 (2017).
Finkel, R. S. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388, 3017–3026 (2016).
Bormann, J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur. J. Pharmacol. 166, 591–592 (1989).
Kornhuber, J., Bormann, J., Retz, W., Hubers, M. & Riederer, P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur. J. Pharmacol. 166, 589–590 (1989).
Chohan, M. O., Khatoon, S., Iqbal, I. G. & Iqbal, K. Involvement of I2 PP2A in the abnormal hyperphosphorylation of tau and its reversal by memantine. FEBS Lett. 580, 3973–3979 (2004).
Miltner, F. O. Use of symptomatic therapy with memantine in cerebral coma. II. Development of stretch synergisms in coma with brain stem symptoms. Arzneimittelforschung 32, 1271–1273 (1982).
Miltner, F. O. Use of symptomatic therapy with memantine in cerebral coma. I. Correlation of coma stages and EEG spectral paters. Arzneimittelforschung 32, 1268–1270 (1982).
Jiang, J. & Jiang, H. Efficacy and adverse effects of memantine treatment for Alzheimer’s disease from randomized controlled trials. Neurol. Sci. 36, 1633–1641 (2015).
Matsunaga, S., Kishi, T. & Iwata, N. Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLoS ONE 10, e0123289 (2015).
Kishi, T., Matsunaga, S. & Iwata, N. Memantine for the treatment of frontotemporal dementia: a meta-analysis. Neuropsychiatr. Dis. Treat. 11, 2883–2885 (2015).
Tsoi, K. K. et al. Combination therapy showed limited superiority over monotherapy for Alzheimer disease: a meta-analysis of 14 randomized trials. J. Am. Med. Dir. Assoc. 17, 863.e1–863.e8 (2016).
Corcoran, N. M. et al. Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model. J. Clin. Neurosci. 17, 1025–1033 (2010).
Rueli, R. H. et al. Selenprotein S reduces endoplasmic reticulum stress-induced phosphorylation of tau: potential selenate mitigation of tau pathology. J. Alzheimers Dis. 55, 749–762 (2017).
van Eersel, J. et al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proc. Natl Acad. Sci. USA 107, 13888–13893 (2010).
Jones, N. C. et al. Targeting hyperphosphorylated tau with sodium selenate suppresses seizures in rodent models. Neurobiol. Dis. 45, 897–901 (2012).
Liu, S. J. et al. Sodium selenate retards epileptogenesis in acquired epilepsy models reversing changes in protein phosphatase 2A and hyperphosphorylated tau. Brain 139, 1919–1938 (2016).
Shultz, S. R. et al. Sodium selenate reduces hyperphosphorylated tau and improves outcomes after traumatic brain injury. Brain 138, 1297–1313 (2015).
Malpas, C. B. et al. A phase IIa randomized control trial of VEL (sodium selenate) in mild–moderate Alzheimer’s disease. J. Alzheimers Dis. 54, 223–232 (2016).
Carlson, B. A., Dubay, M. M., Sausville, E. A., Brizuela, L. & Worland, P. J. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 56, 2973–2978 (1996).
Meijer, L. et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527–536 (1997).
Mapelli, M. et al. Mechanism of CDK5/p25 binding by CDK inhibitors. J. Med. Chem. 48, 671–679 (2005).
Wu, J., Stoica, B. A. & Faden, A. I. Cell cycle activation and spinal cord injury. Neurotherapeutics 8, 221–228 (2011).
Khalil, H. S., Mitev, V., Vlaykova, T., Cavicchi, L. & Zhelev, N. Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance. J. Biotechnol. 202, 40–49 (2015).
Asghar, U., Witkiewicz, A. K., Turner, N. C. & Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 14, 130–146 (2015).
Dominguez, J. M. et al. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J. Biol. Chem. 287, 893–904 (2012).
Martinez, A., Alonso, M., Castro, A., Perez, C. & Moreno, F. J. First non-ATP competitive glycogen synthase kinase 3 β (GSK-3β) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease. J. Med. Chem. 45, 1292–1299 (2002).
DaRocha-Souto, B. et al. Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer’s disease. Neurobiol. Dis. 45, 425–437 (2012).
Sereno, L. et al. A novel GSK-3β inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol. Dis 35, 359–367 (2009).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00948259 (2009).
del Ser, T. et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimers Dis. 33, 205–215 (2013).
Lovestone, S. et al. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis. 45, 75–88 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01049399 (2012).
Tolosa, E. et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov. Disord. 29, 470–478 (2014).
Stambolic, V., Ruel, L. & Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6, 1664–1668 (1996).
Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996).
Forlenza, O. V., De-Paula, V. J. & Diniz, B. S. Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450 (2014).
Forlenza, O. V. et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br. J. Psychiatry 198, 351–356 (2011).
Nunes, M. A., Viel, T. A. & Buck, H. S. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr. Alzheimer Res. 10, 104–107 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02601859 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02862210 (2017).
Min, S. W. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat. Med. 21, 1154–1162 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02422485 (2017).
Sandhu, P. et al. Pharmacokinetics and pharmacodynamics to support clinical studies of MK-8719: an O-GlcNAcase inhibitor for progressive supranuclear palsy [abstract]. Alzheimers Dement. 12 (Suppl.), P4–036 (2016).
[No authors listed.] Alectos Therapeutics announces FDA orphan drug designation for MK-8719: an investigational small-molecule OGA inhibitor for treatment of progressive supranuclear palsy. Alectos http://alectos.com/content/alectos-therapeutics-announces-fda-orphan-drug-designation-mk-8719-investigational-small-molecule-oga-inhibitor-treatment-progressive-supranuclear-palsy/ (2016).
Rohn, T. T. The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities. Apoptosis 15, 1403–1409 (2010).
Panza, F. et al. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. Biomed. Res. Int. 2016, 3245935 (2016).
Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M. & Harrington, C. R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl Acad. Sci. USA 93, 11213–11218 (1996).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01253122 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00515333 (2008).
Wischik, C. M. et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J. Alzheimers Dis. 44, 705–720 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00684944 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01689233 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01689246 (2018).
Gauthier, S. 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. Lancet 388, 2873–2884 (2016).
Fagan, T. In first phase 3 trial, the tau drug LMTM did not work. Period. Alzforum http://www.alzforum.org/news/conference-coverage/first-phase-3-trial-tau-drug-lmtm-did-not-work-period#show-more (2016).
Fagan, T. Tau inhibitor fails again — subgroup analysis irks clinicians at CTAD. Alzforum http://www.alzforum.org/news/conference-coverage/tau-inhibitor-fails-again-subgroup-analysis-irks-clinicians-ctad (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02245568 (2018).
Hu, S. et al. Clinical development of curcumin in neurodegenerative disease. Expert Rev. Neurother. 15, 629–637 (2015).
Hamaguchi, T., Ono, K. & Yamada, M. Review: Curcumin and Alzheimer’s disease. CNS Neurosci. Ther. 16, 285–297 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00164749 (2008).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00099710 (2009).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00595582 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01383161 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01811381 (2018).
Bollag, D. M. et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 55, 2325–2333 (1995).
Brunden, K. R. et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J. Neurosci. 30, 13861–13866 (2010).
Zhang, B. et al. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J. Neurosci. 32, 3601–3611 (2012).
Barten, D. M. 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. 32, 7137–7145 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01492374 (2014).
Magen, I. & Gozes, I. Microtubule-stabilizing peptides and small molecules protecting axonal transport and brain function: focus on davunetide (NAP). Neuropeptides 47, 489–495 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01110720 (2013).
Boxer, A. L. et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 13, 676–685 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01966666 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02133846 (2016).
Fitzgerald, D. P. et al. TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol. Cancer Ther. 11, 1959–1967 (2012).
McQuade, J. L. et al. A phase I study of TPI 287 in combination with temozolomide for patients with metastatic melanoma. Melanoma Res. 26, 604–608 (2016).
Mitchell, D. et al. A phase 1 trial of TPI 287 as a single agent and in combination with temozolomide in patients with refractory or recurrent neuroblastoma or medulloblastoma. Pediatr. Blood Cancer 63, 39–46 (2016).
Wachtel, H. Potential antidepressant activity of rolipram and other selective cyclic adenosine 3ʹ,5ʹ-monophosphate phosphodiesterase inhibitors. Neuropharmacology 22, 267–272 (1983).
Myeku, N. et al. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP–PKA signaling. Nat. Med. 22, 46–53 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02648672 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02840279 (2017).
Lobello, K., Ryan, J. M., Liu, E., Rippon, G. & Black, R. Targeting beta amyloid: a clinical review of immunotherapeutic approaches in Alzheimer’s disease. Int. J. Alzheimers Dis. 2012, 628070 (2012).
Valera, E., Spencer, B. & Masliah, E. Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics 13, 179–189 (2016).
Abushouk, A. I. et al. Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials. BMC Neurol. 17, 66 (2017).
Penninkilampi, R., Brothers, H. M. & Eslick, G. D. Safety and efficacy of anti-amyloid-β immunotherapy in Alzheimer’s disease: a systematic review and meta-analysis. J. Neuroimmune Pharmacol. 12, 194–203 (2017).
Wisniewski, T. & Drummond, E. Developing therapeutic vaccines against Alzheimer’s disease. Expert Rev. Vaccines 15, 401–415 (2016).
Panza, F., Solfrizzi, V., Imbimbo, B. P. & Logroscino, G. Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return? Expert Opin. Biol. Ther. 14, 1465–1476 (2014).
Serrano-Pozo, A. et al. Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology. Brain 133, 1312–1327 (2010).
Boche, D., Denham, N., Holmes, C. & Nicoll, J. A. Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis. Acta Neuropathol. 120, 369–384 (2010).
Boche, D. et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Aβ42 immunisation in Alzheimer’s disease. Acta Neuropathol. 120, 13–20 (2010).
Blennow, K. et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch. Neurol. 69, 1002–1010 (2012).
Salloway, S. et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061–2070 (2009).
Vandenberghe, R. et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res. Ther. 8, 18 (2016).
Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007).
Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem. 118, 658–667 (2011).
Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. Alzheimers Dement. 2 (Suppl.), O2-05-04 (2006).
Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).
Bi, M., Ittner, A., Ke, Y. D., Gotz, J. & Ittner, L. M. Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS ONE 6, e26860 (2011).
Theunis, C. et al. Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau. P301L mice that model tauopathy. PLoS ONE 8, e72301 (2013).
Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J. Neurosci. 30, 16559–16566 (2010).
Troquier, L. et al. Targeting phospho-Ser422 by active tau immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr. Alzheimer Res. 9, 397–405 (2012).
Rajamohamedsait, H., Rasool, S., Rajamohamedsait, W., Lin, Y. & Sigurdsson, E. M. Prophylactic active tau immunization leads to sustained reduction in both tau and amyloid-β pathologies in 3xTg mice. Sci. Rep. 7, 17034 (2017).
Boimel, M. et al. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp. Neurol. 224, 472–485 (2010).
Davtyan, H. et al. MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice. Vaccine 35, 2015–2024 (2017).
Selenica, M. L. et al. Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis. J. Neuroinflamm. 11, 152 (2014).
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. 6, 44 (2014).
Ando, K. et al. Vaccination with Sarkosyl insoluble PHF-tau decrease neurofibrillary tangles formation in aged tau transgenic mouse model: a pilot study. J. Alzheimers Dis. 40 (Suppl. 1), S135–S145 (2014).
Rosenmann, H. et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch. Neurol. 63, 1459–1467 (2006).
Rozenstein-Tsalkovich, L. et al. Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation. Exp. Neurol. 248, 451–456 (2013).
Chai, X. et al. Passive immunization with anti-tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression. J. Biol. Chem. 286, 34457–34467 (2011).
Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013).
Congdon, E. E. 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 11, 62–86 (2016).
Gu, J., Congdon, E. E. & Sigurdsson, E. M. Two novel tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce tau protein pathology. J. Biol. Chem. 288, 33081–33095 (2013).
Ittner, A. et al. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J. Neurochem. 132, 135–145 (2015).
Krishnamurthy, P. K., Deng, Y. & Sigurdsson, E. M. Mechanistic studies of antibody-mediated clearance of tau aggregates using an ex vivo brain slice model. Front. Psychiatry 2, 59 (2011).
Liu, W. et al. Vectored intracerebral immunization with the anti-tau monoclonal antibody PHF1 markedly reduces tau pathology in mutant tau transgenic mice. J. Neurosci. 36, 12425–12435 (2016).
Sankaranarayanan, S. et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS ONE 10, e0125614 (2015).
Subramanian, S., Savanur, G. & Madhavadas, S. Passive immunization targeting the N-terminal region of phosphorylated tau (residues 68–71) improves spatial memory in okadaic acid induced tauopathy model rats. Biochem. Biophys. Res. Commun. 483, 585–589 (2017).
Dai, C. L. 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. 122, 607–617 (2015).
Yanamandra, K. et al. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci. Transl Med. 9, eaal2029 (2017).
Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M. & Diamond, M. I. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012).
Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013).
Dai, C. L., Tung, Y. C., Liu, F., Gong, C. X. & Iqbal, K. Tau passive immunization inhibits not only tau but also Aβ pathology. Alzheimers Res. Ther. 9, 1 (2017).
Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015).
Castillo-Carranza, D. L. et al. Passive immunization with tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260–4272 (2014).
Castillo-Carranza, D. L. et al. Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J. Alzheimers Dis. 40 (Suppl. 1), S97–S111 (2014).
d’Abramo, C., Acker, C. M., Jimenez, H. T. & Davies, P. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS ONE 8, e62402 (2013).
Kondo, A. et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523, 431–436 (2015).
d’Abramo, C., Acker, C. M., Jimenez, H. & Davies P. Passive immunization in JNPL3 transgenic mice using an array of phospho-tau specific antibodies. PLoS ONE 10, e0135774 (2015).
Walls, K. C. et al. p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice. Neurosci. Lett. 575, 96–100 (2014).
Lee, S. H. et al. Antibody-mediated targeting of tau in vivo does not require effector function and microglial engagement. Cell Rep. 16, 1690–1700 (2016).
Umeda, T. et al. Passive immunotherapy of tauopathy targeting pSer413-tau: a pilot study in mice. Ann. Clin. Transl Neurol. 2, 241–255 (2015).
Collin, L. et al. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 137, 2834–2846 (2014).
Nisbet, R. M. et al. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140, 1220–1330 (2017).
Ising, C. et al. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J. Exp. Med. 214, 1227–1238 (2017).
Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer’s disease. Trends Mol. Med. 21, 394–402 (2015).
Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013).
Sigurdsson, E. M. Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. J. Alzheimers Dis. 15, 157–168 (2008).
Krishnaswamy, S. et al. Antibody-derived in vivo imaging of tau pathology. J. Neurosci. 34, 16835–16850 (2014).
Fuller, J. P., Stavenhagen, J. B. & Teeling, J. L. New roles for Fc receptors in neurodegeneration — the impact on immunotherapy for Alzheimer’s disease. Front. Neurosci. 8, 235 (2014).
van der Kleij, H. et al. Evidence for neuronal expression of functional Fc (ε and γ) receptors. J. Allergy Clin. Immunol. 125, 757–760 (2010).
McEwan, W. A. et al. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc. Natl Acad. Sci. USA 114, 574–579 (2017).
Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 113 (2014).
Sigurdsson, E. M., Wisniewski, T. & Frangione, B. Infectivity of amyloid diseases. Trends Mol. Med. 8, 411–413 (2002).
Herukka, S. K. et al. Amyloid-β and tau dynamics in human brain interstitial fluid in patients with suspected normal pressure hydrocephalus. J. Alzheimers Dis. 46, 261–269 (2015).
Croft, C. L. et al. Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures. Cell Death Dis. 8, e2671 (2017).
Sigurdsson, E. M. Tau immunotherapy. Neurodegener. Dis. 16, 34–38 (2016).
Yanamandra, K. et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann. Clin. Transl Neurol. 2, 278–288 (2015).
Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R. & Novak, M. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res. Ther. 6, 45 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01850238 (2015).
Novak, P. 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. 16, 123–134 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02031198 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02579252 (2017).
Ondrus, M. & Novak, P. Design of the phase II clinical study of the tau vaccine AADvac1 in patients with mild Alzheimer’s disease. Neurobiol. Aging 39 (Suppl. 1), S26 (2016).
International Clincal Trials Registry Platform. ISRCTN.com http://www.isrctn.com/ISRCTN13033912 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02281786 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02294851 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02460094 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02658916 (2018).
[No authors listed.] Biogen licenses phase 2 anti-tau antibody from Bristol-Myers Squibb. Biogen http://media.biogen.com/press-release/corporate/biogen-licenses-phase-2-anti-tau-antibody-bristol-myers-squibb (2017).
West, T. et al. Safety, tolerability and pharmacokinetics of ABBV-8E12, a humanized anti-tau monoclonal antibody, in a Phase I, single ascending dose, placebo-controlled study in subjects with progressive supranuclear palsy. J. Prev. Alzheimers Dis. 3, 285 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02985879 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02880956 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02820896 (2017).
Rogers, M. B. Treating tau: finally, clinical candidates are stepping into the ring. Alzforum http://www.alzforum.org/news/conference-coverage/treating-tau-finally-clinical-candidates-are-stepping-ring (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02754830 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03019536 (2018).
Hayashi, M. L., Lu, J., Driver, D. & Alvarado, A. Antibodies to tau and uses thereof. US Patent US20160251420 A1 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03375697 (2018).
Rogers, M. B. To block tau’s proteopathic spread, antibody must attack its mid-region. Alzforum https://www.alzforum.org/news/conference-coverage/block-taus-proteopathic-spread-antibody-must-attack-its-mid-region (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03464227 (2018).
Congdon, E. E., Krishnaswamy, S. & Sigurdsson, E. M. Harnessing the immune system for treatment and detection of tau pathology. J. Alzheimers Dis. 40 (Suppl.1), S113–S121 (2014).
Barthelemy, N. R. et al. differential mass spectrometry profiles of tau protein in the cerebrospinal fluid of patients with Alzheimer’s disease, progressive supranuclear palsy, and dementia with lewy bodies. J. Alzheimers Dis. 51, 1033–1043 (2016).
Barthelemy, N. R. et al. Tau protein quantification in human cerebrospinal fluid by targeted mass spectrometry at high sequence coverage provides insights into its primary structure heterogeneity. J. Proteome Res. 15, 667–676 (2016).
Giacobini, E. & Gold, G. Alzheimer disease therapy — moving from amyloid-β to tau. Nat. Rev. Neurol. 9, 677–686 (2013).
Acknowledgements
E.M.S. was supported by NIH grants R01 NS077239 and R01 AG032611 and a pilot grant from the Michael J. Fox Foundation. E.E.C. was supported by a grant from the Alzheimer’s Association.
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Both authors researched data for the article, made substantial contributions to discussion of the content, wrote the article, developed the figures and tables and reviewed and edited the manuscript before submission.
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E.M.S. is an inventor on various patents on immunotherapies and related diagnostics that are assigned to New York University. Some of those focusing on the tau protein are licensed to and are being co-developed with H. Lundbeck A/S. E.E.C. declares no competing interests.
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Congdon, E.E., Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14, 399–415 (2018). https://doi.org/10.1038/s41582-018-0013-z
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DOI: https://doi.org/10.1038/s41582-018-0013-z
