Reader TTS

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 * Therapies for Alzheimer disease in clinical trials are gradually shifting from amyloid-β

(Aβ)-targeting to tau-targeting approaches. * 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. * Most of the tau-targeting approaches that are currently in clinical trials are immunotherapies. * 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. * Eventually, with continued

improvements in diagnostics, both Aβ and tau are likely to be targeted prophylactically for clearance. Access through your institution Buy or subscribe This is a preview of subscription

content, access via your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access

subscription $29.99 / 30 days cancel any time Learn more Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this

article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in

* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS TAU-TARGETING THERAPIES FOR ALZHEIMER DISEASE: CURRENT STATUS AND

FUTURE DIRECTIONS Article 24 October 2023 THE AMYLOID HYPOTHESIS IN ALZHEIMER DISEASE: NEW INSIGHTS FROM NEW THERAPEUTICS Article 17 February 2022 AMYLOID Β-BASED THERAPY FOR ALZHEIMER’S

DISEASE: CHALLENGES, SUCCESSES AND FUTURE Article Open access 30 June 2023 REFERENCES * Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. _Alzheimers Dement._ 12, 459–509

(2016). Article  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central 

Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  *

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).

Article  PubMed  PubMed Central  CAS  Google Scholar  * Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. _Neuron_ 67, 953–966 (2010). Article 

PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar

  * Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. _Acta Neuropathol._ 82, 239–259 (1991). Article  PubMed  CAS  Google Scholar  * Braak, H. & Braak,

E. Frequency of stages of Alzheimer-related lesions in different age categories. _Neurobiol. Aging_ 18, 351–357 (1997). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed

Central  Google Scholar  * Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. _Acta Neuropathol._ 128, 755–766 (2014). Article  PubMed

  PubMed Central  CAS  Google Scholar  * Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. _J. Biol. Chem._ 261, 6084–6089

(1986). PubMed  CAS  Google Scholar  * Kidd, M. Paired helical filaments in electron microscopy of Alzheimer’s disease. _Nature_ 197, 192–193 (1963). Article  PubMed  CAS  Google Scholar  *

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). Article  PubMed  CAS  Google Scholar  * Arima, K. Ultrastructural characteristics of tau filaments in tauopathies: immuno-electron microscopic demonstration of tau filaments in

tauopathies. _Neuropathology_ 26, 475–483 (2006). Article  PubMed  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  *

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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Noble, W., Hanger, D. P., Miller, C. C. & Lovestone, S. The importance of tau

phosphorylation for neurodegenerative diseases. _Front. Neurol._ 4, 83 (2013). Article  PubMed  PubMed Central  CAS  Google Scholar  * Lindwall, G. & Cole, R. D. Phosphorylation affects

the ability of tau protein to promote microtubule assembly. _J. Biol. Chem._ 259, 5301–5305 (1984). PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Hanger, D. P. & Wray, S. Tau cleavage and tau aggregation in

neurodegenerative disease. _Biochem. Soc. Trans._ 38, 1016–1020 (2010). Article  PubMed  CAS  Google Scholar  * Kimura, T. et al. Sequential changes of tau-site-specific phosphorylation

during development of paired helical filaments. _Dementia_ 7, 177–181 (1996). PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  *

Shukla, V., Skuntz, S. & Pant, H. C. Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. _Arch. Med. Res._ 43, 655–662 (2012). Article  PubMed  PubMed Central  CAS 

Google Scholar  * Tell, V. & Hilgeroth, A. Recent developments of protein kinase inhibitors as potential AD therapeutics. _Front. Cell. Neurosci._ 7, 189 (2013). Article  PubMed  PubMed

Central  CAS  Google Scholar  * 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). PubMed  Google Scholar  * Liu, S. L. et al. The role of Cdk5 in Alzheimer’s disease. _Mol. Neurobiol._ 53, 4328–4342 (2016). Article  PubMed  CAS  Google Scholar 

* 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).

Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Sontag, J. M. & Sontag, E. Protein phosphatase 2A dysfunction in Alzheimer’s disease.

_Front. Mol. Neurosci._ 7, 16 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * Wang, Y. & Mandelkow, E. Tau in physiology and pathology. _Nat. Rev. Neurosci._ 17, 5–21

(2016). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Guo, T., Noble, W. & Hanger, D. P. Roles of tau protein in health and disease. _Acta

Neuropathol._ 133, 665–704 (2017). Article  PubMed  PubMed Central  CAS  Google Scholar  * Zhao, X. et al. Caspase-2 cleavage of tau reversibly impairs memory. _Nat. Med._ 22, 1268–1276

(2016). Article  PubMed  CAS  Google Scholar  * Jadhav, S. et al. Truncated tau deregulates synaptic markers in rat model for human tauopathy. _Front. Cell. Neurosci._ 9, 24 (2015). Article

  PubMed  PubMed Central  CAS  Google Scholar  * Liu, F. et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. _Brain_ 132, 1820–1832

(2009). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Zhang, F. et al. Posttranslational

modifications of α-tubulin in Alzheimer disease. _Transl Neurodegener._ 4, 9 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * Stokin, G. B. et al. Axonopathy and transport

deficits early in the pathogenesis of Alzheimer’s disease. _Science_ 307, 1282–1288 (2005). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed

Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. _Science_ 330, 198

(2010). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * Vazquez,

A. Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases. _PLOS ONE_ 8, e63822 (2013). Article  PubMed  PubMed Central  CAS 

Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  *

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). Article  PubMed  CAS  Google Scholar  * Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage.

_Front. Aging Neurosci._ 9, 83 (2017). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Fagan, A. M. et al. Longitudinal change

in CSF biomarkers in autosomal-dominant Alzheimer’s disease. _Sci. Transl Med._ 6, 226ra30 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google

Scholar  * Hu, W. T., Trojanowski, J. Q. & Shaw, L. M. Biomarkers in frontotemporal lobar degenerations — progress and challenges. _Prog. Neurobiol._ 95, 636–648 (2011). Article  PubMed

  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Mufson, E. J., Ward, S. & Binder, L. Prefibrillar tau oligomers in mild cognitive impairment and

Alzheimer’s disease. _Neurodegener. Dis._ 13, 151–153 (2014). Article  PubMed  CAS  Google Scholar  * Flach, K. et al. Tau oligomers impair artificial membrane integrity and cellular

viability. _J. Biol. Chem._ 287, 43223–43233 (2012). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * Goedert, M. &

Spillantini, M. G. Propagation of Tau aggregates. _Mol. Brain_ 10, 18 (2017). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  CAS  Google

Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Zare-Shahabadi, A., Masliah, E., Johnson, G. V. & Rezaei, N. Autophagy in Alzheimer’s disease. _Rev. Neurosci._ 26, 385–395

(2015). Article  PubMed  PubMed Central  Google Scholar  * Nixon, R. A. The role of autophagy in neurodegenerative disease. _Nat. Med._ 19, 983–997 (2013). Article  PubMed  CAS  Google

Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar

  * 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). Article  PubMed  CAS  Google Scholar  * 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). PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google

Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Wang, Y. & Mandelkow, E. Degradation of tau protein by autophagy and proteasomal pathways.

_Biochem. Soc. Trans._ 40, 644–652 (2012). Article  PubMed  CAS  Google Scholar  * Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s

disease. _Science_ 235, 1641–1644 (1987). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Morawe, T., Hiebel, C., Kern, A. & Behl, C. Protein homeostasis, aging and Alzheimer’s disease. _Mol. Neurobiol._ 46,

41–54 (2012). Article  PubMed  PubMed Central  CAS  Google Scholar  * Gurney, M. E., D’Amato, E. C. & Burgin, A. B. Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s

disease. _Neurotherapeutics_ 12, 49–56 (2015). Article  PubMed  CAS  Google Scholar  * Sweeney, P. et al. Protein misfolding in neurodegenerative diseases: implications and strategies.

_Transl Neurodegener._ 6, 6 (2017). Article  PubMed  PubMed Central  CAS  Google Scholar  * Deger, J. M., Gerson, J. E. & Kayed, R. The interrelationship of proteasome impairment and

oligomeric intermediates in neurodegeneration. _Aging Cell_ 14, 715–724 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Ke, Y. D. et al. Lessons from tau-deficient mice. _Int. J.

Alzheimers Dis._ 2012, 873270 (2012). PubMed  PubMed Central  Google Scholar  * Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. _Nat. Rev.

Genet._ 16, 543–552 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * Zuckerman, J. E. & Davis, M. E. Clinical experiences with systemically administered siRNA-based

therapeutics in cancer. _Nat. Rev. Drug Discov._ 14, 843–856 (2015). Article  PubMed  CAS  Google Scholar  * Corey, D. R. Nusinersen, an antisense oligonucleotide drug for spinal muscular

atrophy. _Nat. Neurosci._ 20, 497–499 (2017). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Bormann, J. Memantine is a potent blocker of _N_-methyl-D-aspartate (NMDA) receptor

channels. _Eur. J. Pharmacol._ 166, 591–592 (1989). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  CAS  Google

Scholar  * 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). PubMed  CAS  Google Scholar  * 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). PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Matsunaga, S., Kishi, T. & Iwata, N. Memantine monotherapy for Alzheimer’s disease:

a systematic review and meta-analysis. _PLoS ONE_ 10, e0123289 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * Kishi, T., Matsunaga, S. & Iwata, N. Memantine for the

treatment of frontotemporal dementia: a meta-analysis. _Neuropsychiatr. Dis. Treat._ 11, 2883–2885 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article 

Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  *

Jones, N. C. et al. Targeting hyperphosphorylated tau with sodium selenate suppresses seizures in rodent models. _Neurobiol. Dis._ 45, 897–901 (2012). Article  PubMed  CAS  Google Scholar  *

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).

Article  PubMed  Google Scholar  * Shultz, S. R. et al. Sodium selenate reduces hyperphosphorylated tau and improves outcomes after traumatic brain injury. _Brain_ 138, 1297–1313 (2015).

Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google

Scholar  * Mapelli, M. et al. Mechanism of CDK5/p25 binding by CDK inhibitors. _J. Med. Chem._ 48, 671–679 (2005). Article  PubMed  CAS  Google Scholar  * Wu, J., Stoica, B. A. & Faden,

A. I. Cell cycle activation and spinal cord injury. _Neurotherapeutics_ 8, 221–228 (2011). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed

  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Dominguez, J. M. et al. Evidence for irreversible inhibition of glycogen synthase kinase-3β by

tideglusib. _J. Biol. Chem._ 287, 893–904 (2012). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed

  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). PubMed  Google Scholar  * Lovestone, S. et al. A phase II trial

of tideglusib in Alzheimer’s disease. _J. Alzheimers Dis._ 45, 75–88 (2015). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar 

* 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). Article  PubMed  Google Scholar  * 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). PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Google Scholar  * [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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google

Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  *

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). Article  PubMed  CAS  Google Scholar  * Hamaguchi, T., Ono, K. & Yamada, M. Review: Curcumin and Alzheimer’s disease. _CNS Neurosci. Ther._ 16, 285–297 (2010). Article  PubMed 

CAS  Google Scholar  * 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). PubMed  CAS  Google Scholar  *

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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS 

Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Wachtel, H.

Potential antidepressant activity of rolipram and other selective cyclic adenosine 3ʹ,5ʹ-monophosphate phosphodiesterase inhibitors. _Neuropharmacology_ 22, 267–272 (1983). Article  PubMed 

CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  CAS  Google

Scholar  * 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). Article  PubMed  PubMed

Central  Google Scholar  * 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). Article  PubMed  Google Scholar  * Wisniewski, T. & Drummond, E. Developing therapeutic vaccines against Alzheimer’s

disease. _Expert Rev. Vaccines_ 15, 401–415 (2016). PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article

  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Salloway, S. et al. A phase 2 multiple ascending dose trial of bapineuzumab in

mild to moderate Alzheimer disease. _Neurology_ 73, 2061–2070 (2009). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. _Alzheimers Dement._ 2 (Suppl.), O2-05-04 (2006). Google Scholar  *

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). Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  *

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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS 

Google Scholar  * Boimel, M. et al. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. _Exp. Neurol._ 224, 472–485 (2010). Article  PubMed 

CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Selenica, M. L. et al. Epitope analysis following active immunization with tau proteins reveals

immunogens implicated in tau pathogenesis. _J. Neuroinflamm._ 11, 152 (2014). Article  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Rosenmann, H. et al. Tauopathy-like

abnormalities and neurologic deficits in mice immunized with neuronal tau protein. _Arch. Neurol._ 63, 1459–1467 (2006). Article  PubMed  Google Scholar  * Rozenstein-Tsalkovich, L. et al.

Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation. _Exp. Neurol._ 248, 451–456 (2013). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed

Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Ittner, A. et al. Tau-targeting passive immunization modulates

aspects of pathology in tau transgenic mice. _J. Neurochem._ 132, 135–145 (2015). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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).

Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article

  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Yanamandra, K. et al. Anti-tau antibody administration increases

plasma tau in transgenic mice and patients with tauopathy. _Sci. Transl Med._ 9, eaal2029 (2017). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS 

Google Scholar  * 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).

Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Bright, J. et al. Human secreted tau increases amyloid-beta production. _Neurobiol. Aging_ 36,

693–709 (2015). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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).

Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Kondo, A. et al. Antibody against early driver of neurodegeneration _cis_ P-tau blocks brain injury and

tauopathy. _Nature_ 523, 431–436 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Umeda, T. et al. Passive immunotherapy of tauopathy targeting pSer413-tau: a

pilot study in mice. _Ann. Clin. Transl Neurol._ 2, 241–255 (2015). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer’s disease. _Trends Mol. Med._ 21, 394–402 (2015). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Sigurdsson,

E. M. Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. _J. Alzheimers Dis._ 15, 157–168 (2008). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Krishnaswamy, S. et al. Antibody-derived in vivo imaging of tau pathology. _J. Neurosci._ 34, 16835–16850 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). PubMed

  PubMed Central  Google Scholar  * 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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * McEwan, W. A. et al. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. _Proc. Natl Acad. Sci. USA_ 114, 574–579 (2017). Article 

PubMed  PubMed Central  CAS  Google Scholar  * Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. _Front. Cell. Neurosci._ 8, 113 (2014).

PubMed  PubMed Central  Google Scholar  * Sigurdsson, E. M., Wisniewski, T. & Frangione, B. Infectivity of amyloid diseases. _Trends Mol. Med._ 8, 411–413 (2002). Article  PubMed  CAS 

Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Sigurdsson, E. M. Tau immunotherapy. _Neurodegener. Dis._ 16, 34–38 (2016). Article  PubMed  CAS  Google

Scholar  * Yanamandra, K. et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. _Ann. Clin. Transl Neurol._ 2, 278–288 (2015). Article  PubMed  PubMed Central  CAS 

Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  Google

Scholar  * 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). Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed 

CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Giacobini, E. & Gold, G. Alzheimer disease therapy — moving from amyloid-β

to tau. _Nat. Rev. Neurol._ 9, 677–686 (2013). Article  PubMed  CAS  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Neuroscience and Physiology, New York University School of Medicine, New York, NY, USA Erin E. Congdon & Einar M. Sigurdsson * Department of Psychiatry, New York University School of

Medicine, New York, NY, USA Einar M. Sigurdsson Authors * Erin E. Congdon View author publications You can also search for this author inPubMed Google Scholar * Einar M. Sigurdsson View

author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS 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. CORRESPONDING AUTHOR Correspondence to Einar M. Sigurdsson. ETHICS

DECLARATIONS COMPETING INTERESTS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral

with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 12 June 2018 *

Issue Date: July 2018 * DOI: https://doi.org/10.1038/s41582-018-0013-z SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link

Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative