In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils
Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.
Authors
- Kevin A. Murray (ORCID: https://orcid.org/0000-0003-1969-7701)
- Gazmend Elezi (ORCID: https://orcid.org/0000-0003-4087-3431)
- Michael DeTure (ORCID: https://orcid.org/0000-0002-4363-1262)
- Christopher Kwesi O. Williams (ORCID: https://orcid.org/0000-0001-9403-7207)
- Hung‐Kai Hsu (ORCID: https://orcid.org/0000-0001-9347-2290)
- Patrick G. Harran (ORCID: https://orcid.org/0000-0001-8748-5167)
- Jeffrey Zhang (ORCID: https://orcid.org/0000-0002-6617-034X)
- Ke Hou (ORCID: https://orcid.org/0000-0003-3869-2076)
- M.R. Sawaya (ORCID: https://orcid.org/0000-0003-0874-9043)
- Hilda Mirbaha
- Marisa Mekkittikul (ORCID: https://orcid.org/0000-0003-1739-9452)
- Romany Abskharon (ORCID: https://orcid.org/0000-0003-1350-0189)
- Julian P. Whitelegge (ORCID: https://orcid.org/0000-0003-2763-7733)
- David Eisenberg (ORCID: https://orcid.org/0000-0003-2432-5419)
- Sally A. Frautschy (ORCID: https://orcid.org/0000-0003-0194-0363)
- Hope Pan (ORCID: https://orcid.org/0000-0001-6509-6224)
- Tyler Halladay
- Xinyi Cheng (ORCID: https://orcid.org/0000-0001-6402-1263)
- Dennis W. Dickson
- Cansheng Zhu
- Gregory M. Cole
- Kapil Manglani
- Alexander Bombino
- Harry V. Vinters
Institutions
- West Los Angeles College (US)
- John Brown University (US)
- UCLA Health (US)
- WinnMed (US)
- Geriatric Research Education and Clinical Center (US)
- IONICS Mass Spectrometry (Canada) (CA)
- Institute of Molecular Medicine (IN)
- VA Greater Los Angeles Healthcare System (US)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2026-01-05
- DOI
- https://doi.org/10.1021/acschemneuro.5c00940
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00