Tau-directed drug discovery for alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors
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The microtubule-associated protein tau forms insoluble filaments that deposit as neurofibrillary tangles (NFTs) in the brains of those with Alzheimer's disease (AD) and other related neurodegenerative disorders. The presence of both NFTs and amyloid beta (Abeta)-containing senile plaques within the brain is required to confirm the diagnosis of AD. However, the demonstration that familial AD can be caused by mutations that result in increased Abeta production has resulted in AD drug discovery strategies that are largely focused on reducing brain Abeta levels, with substantially less emphasis on tau-directed approaches. This trend may be changing, as there are an increasing number of research programs that are exploring ways to reduce NFTs in AD and related tauopathies. We briefly review recent advances in tau-based drug discovery, with an emphasis on the identification of compounds that inhibit the assembly of tau into multimers and fibrils.
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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 Brunden et al., 2010
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- Authors
- Brunden, K. R., Ballatore, C., Crowe, A., Smith, Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Brunden, Kurt R.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 223
- Issue
- 2
- Pages
- 304-310
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC2864354
- OpenAlex
- W1969483518
- Cited by
- 93
- References
- 78
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 9 · 2014: 9 · 2013: 5 · 2012: 10
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P01 AG09215, P01 AG11542, P01 AG14382, P01 AG14449, P01 AG17586, P01 NS-044233, P30 AG10124, PO1 AG19724, UO1 AG24904)
- 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
- tau protein, Alzheimer's disease, tauopathy, neurofibrillary tangles, tau fibrils, drug discovery, amyloid-beta, amyloid plaques, familial Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Humans, Neurofibrillary Tangles, tau Proteins, Tauopathies, Drug Discovery
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