Development of tau aggregation inhibitors for alzheimer's disease
Abstract
Abstract Small molecules against Alzheimer's : The pathological aggregation of the tau protein is a major hallmark of neurodegenerative diseases such as Alzheimer's disease. The inhibition or reversal of tau aggregation is a potential therapeutic strategy that is currently undergoing clinical trials. The image shows pathological fibers assembled from tau protein, which are the main components of the neurofibrillary tangles of Alzheimer's disease. magnified image A variety of human diseases are suspected to be directly linked to protein misfolding. Highly organized protein aggregates, called amyloid fibrils, and aggregation intermediates are observed; these are considered to be mediators of cellular toxicity and thus attract a great deal of attention from investigators. Neurodegenerative pathologies such as Alzheimer's disease account for a major part of these protein misfolding diseases. The last decade has witnessed a renaissance of interest in inhibitors of tau aggregation as potential disease‐modifying drugs for Alzheimer's disease and other “tauopathies”. The recent report of a phase II clinical trial with the tau aggregation inhibitor MTC could hold promise for the validation of the concept. This Review summarizes the available data concerning small‐molecule inhibitors of tau aggregation from a medicinal chemistry point of view.
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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 Bulic et al., 2009
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Alzheimer’s disease: Clinical trials and drug development
Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., & Kivipelto, M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70119-8 · Cited by 1,217 · see citing works
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
Silva, M. C., Ferguson, F. M., Cai, Q., Donovan, K. A., Nandi, G., Patnaik, D., Zhang, T., Huang, H.-T., Lucente, D. E., Dickerson, B. C., et al. (2019) · eLife · doi:10.7554/elife.45457 · Cited by 283 · see citing works
Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-Proteasome Degradation
Chu, T.-T., Gao, N., Li, Q.-Q., Chen, P.-G., Yang, X.-F., Chen, Y.-X., Zhao, Y.-F., & Li, Y.-M. (2016) · Cell Chemical Biology · doi:10.1016/j.chembiol.2016.02.016 · Cited by 247 · see citing works
Brahmi (Bacopa monnieri): An ayurvedic herb against the Alzheimer's disease
Dubey, T., & Chinnathambi, S. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.108153 · Cited by 151 · see citing works
Rational therapeutic approaches to progressive supranuclear palsy
Stamelou, M., de Silva, R., Arias-Carrion, O., Boura, E., Hollerhage, M., Oertel, W. H., Muller, U., & Hoglinger, G. U. (2010) · Brain · doi:10.1093/brain/awq115 · Cited by 91 · see citing works
The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics
Pritchard, S. M., Dolan, P. J., Vitkus, A., & Johnson, G. V. W. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01273.x · Cited by 89 · see citing works
Korábečný, J., Nepovimová, E., Cikánková, T., Špilovská, K., Vašková, L., Mezeiová, E., Kuča, K., & Hroudová, J. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2017.06.034 · Cited by 64 · see citing works
γ-Secretase and its modulators: Twenty years and beyond
Xia, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.02.011 · Cited by 54 · see citing works
Liquid-liquid phase separation in Alzheimer’s disease
Fu, Q., Zhang, B., Chen, X., & Chu, L. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02407-3 · Cited by 33 · see citing works
Yuan, X., Wang, Z., Zhang, L., Sui, R., & Khan, S. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.05.041 · Cited by 22 · see citing works
- Authors
- Bulic, B., Pickhardt, M., Schmidt, B., Mandelkow, E., Waldmann, H., & Mandelkow, E.
- Affiliations
- TU Dortmund University (DE)
- Deutsches Elektronen-Synchrotron DESY (DE)
- Technische Universität Darmstadt (DE)
- Corresponding author
- Bulic, Bruno
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2009-02-17
- Volume
- 48
- Issue
- 10
- Pages
- 1740-1752
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2042485050
- Cited by
- 286
- References
- 94
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 17 · 2023: 8 · 2022: 14 · 2021: 14 · 2020: 17 · 2019: 17 · 2018: 17 · 2017: 10 · 2016: 14 · 2015: 18 · 2014: 12 · 2013: 27 · 2012: 14
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau aggregation inhibitors, Alzheimer's disease, tauopathy, tau aggregation, neurofibrillary tangles, amyloid fibrils, protein misfolding, small molecule inhibitors, MTC, disease-modifying drugs, medicinal chemistry
- MeSH terms
- Alzheimer Disease, Amyloid, Humans, Thiazoles, Databases, Factual, Amyloid beta-Peptides, tau Proteins, Tauopathies, Benzothiazoles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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