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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation.
Shannon E Hill1,2, David Beaulieu-Abdelahad1,2, Andrea Lemus3
1Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
ACS Chemical Biology
|May 5, 2023
Summary
New Hsp70 inhibitors targeting heat shock protein 70 kDa (Hsp70) reduce tau accumulation in neurodegenerative diseases. Hydrophilic benzothiazole analogs show promise in reducing phosphorylated tau, potentially aiding Alzheimer's disease treatment.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Accumulation of the microtubule-associated protein tau (tau) into neuronal tangles characterizes neurodegenerative tauopathies like Alzheimer's disease (AD).
- Aberrant tau phosphorylation is linked to tau aggregates in AD.
- Heat shock protein 70 kDa (Hsp70) family chaperones interact with tau, influencing its clearance and aggregation.
- Inhibitors of Hsp70 chaperones can decrease tau accumulation, including phosphorylated tau.
Purpose of the Study:
- To synthesize and evaluate novel analogs of the rhodacyanine inhibitor JG-98.
- To assess the efficacy of these analogs in reducing tau accumulation, particularly phosphorylated tau.
- To investigate the relationship between compound hydrophilicity and efficacy in reducing phosphorylated tau.
Main Methods:
- Eight analogs of JG-98 were synthesized.
- Inhibition of cytosolic heat shock cognate 70 protein (Hsc70) ATPase activity was measured.
- Tau, aggregated tau, and phosphorylated tau levels were assessed in cultured cells.
- Blood-brain barrier penetration and tau reduction were evaluated in vivo and in an ex vivo brain slice model for three selected compounds.
Main Results:
- Several synthesized compounds inhibited Hsc70 ATPase activity and reduced total, aggregated, and phosphorylated tau in cultured cells.
- Compound AL69, with the lowest clogP and membrane retention, effectively reduced phosphorylated tau accumulation in an ex vivo brain slice model.
- Benzothiazole substitutions on JG-98 that increase hydrophilicity correlated with improved efficacy in reducing phosphorylated tau.
Conclusions:
- Novel JG-98 analogs demonstrate potential as Hsp70 inhibitors for reducing tau pathology.
- Increased hydrophilicity, achieved through benzothiazole substitutions, may enhance the therapeutic efficacy of these inhibitors.
- These findings suggest a promising strategy for developing treatments for tauopathies like Alzheimer's disease.
