Tau-Centric targets and drugs in clinical development for the treatment of alzheimer's disease
Open accessAbstract
The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT(+)). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.
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Methylene blue blocks the polymerization of tau in vitro by trapping tau monomers in an aggregation-incompetent conformation.
“Methylene blue blocks the polymerization of tau in vitro by trapping the tau monomers in an aggregation-incompetent conformation137,138.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [137]
Anti-tau immunotherapy has shown promise in animal models, but antibody affinity and specificity as well as strong immune responses pose critical challenges.
“Moreover, anti-tau immunotherapy has shown promise in animal models, but antibody affinity and specificity as well as strong immune responses pose critical challenges”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Panza et al., 2016
Molecular mechanisms leading to neuronal toxicity and death in tauopathies are still not entirely understood.
“One of the major bottlenecks in developing effective therapies for tauopathies resides in the fact that molecular mechanisms leading to neuronal toxicity and death are still not entirely understood”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Panza et al., 2016
Current investigative tau-directed therapeutics have focused on aggregation inhibitors, activators of protein clearance through autophagy, and inhibition of tau kinases.
“Current investigative tau-directed therapeutics have focused on aggregation inhibitors (Brunden et al., 2010; Panza et al., 2016; Bulic et al., 2009), activators of protein clearance through autophagy (Boland et al., 2008; Krüger et al., 2012; Medina, 2018; Wang and Mandelkow, 2012; Rubinsztein et al., 2015), and inhibition of tau kinases (Dolan and Johnson, 2010; Medina, 2018).”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Panza et al., 2016
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References 160 · Cited by 195
Research works printed but not linked: 1
- [89]Buée L. Bussière T. Buée-Scherrer V. Delacourte A. Hof P. R. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders Brain Research Reviews 2000 33 1 95 130 10.1016/s0165-0173(00)00019-9 2-s2.0-0033850407 10967355 · DOI
- Authors
- Panza, F., Solfrizzi, V., Seripa, D., Imbimbo, B. P., Lozupone, M., Santamato, A., Zecca, C., Barulli, M. R., Bellomo, A., Pilotto, A., Daniele, A., Greco, A., & Logroscino, G.
- Affiliations
- Casa Sollievo della Sofferenza (IT)
- University of Bari Aldo Moro (IT)
- Chiesi (Italy) (IT)
- University of Foggia (IT)
- Ente Ospedaliero Ospedali Galliera (IT)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Panza, Francesco
- ORCID
- Venue
- BioMed Research International
- Publisher
- Wiley
- Published
- 2016
- Volume
- 2016
- Pages
- 1-15
- ISSN
- 1110-7243 (ISSN-L)
- 2314-6133
- 2314-6141
- PMC
- PMC4939203
- OpenAlex
- W2463554686
- Cited by
- 195
- References
- 160
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 13 · 2022: 18 · 2021: 16 · 2020: 23 · 2019: 25 · 2018: 37 · 2017: 20 · 2016: 3
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BioMed Research International (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
- Funders
- Ministero della Salute (2009E4RM4Z)
- Ministero dell’Istruzione, dell’Università e della Ricerca (2009E4RM4Z)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, tau pathology, tau aggregation inhibitors, methylene blue, salsalate, passive immunization, active immunization, behavioral variant frontotemporal dementia, clinical trials
- MeSH terms
- Alzheimer Disease, Brain, Humans, Methylene Blue, tau Proteins, Treatment Outcome, Neuroprotective Agents, Evidence-Based Medicine, Molecular Targeted Therapy
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