Modulating disease-relevant tau oligomeric strains by small molecules.
brain-derived tau oligomers
oligomer
protein aggregation
small molecule
tau aggregation
tau oligomeric strains
tau protein
tauopathy
toxicity
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
30 10 2020
30 10 2020
Historique:
received:
29
05
2020
revised:
23
07
2020
pubmed:
2
8
2020
medline:
30
3
2021
entrez:
2
8
2020
Statut:
ppublish
Résumé
The pathological aggregation of tau plays an important role in Alzheimer's disease and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies o disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTO-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.
Identifiants
pubmed: 32737202
pii: S0021-9258(17)48893-4
doi: 10.1074/jbc.RA120.014630
pmc: PMC7606668
pii:
doi:
Substances chimiques
Biopolymers
0
Small Molecule Libraries
0
tau Proteins
0
Curcumin
IT942ZTH98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14807-14825Subventions
Organisme : NIA NIH HHS
ID : RF1 AG055771
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054025
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG060718
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG060718
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS094557
Pays : United States
Informations de copyright
© 2020 Lo Cascio et al.
Déclaration de conflit d'intérêts
Conflict of interest—R. K., F. L. C., A. P., and A. P. P. are inventors on a patent application on small molecules and tau oligomers. R. K. is an inventor on patents and patent applications on the compositions and methods related to tau oligomers and tau oligomer antibodies.
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