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Modulating Disease-relevant Tau Oligomeric Strains by Small Molecules

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Alzheimer’s diseases (AD) is the most common age-related neurodegenerative disorder affecting millions of people worldwide. AD is one of over 18 different diseases known as tauopathies, characterized by the pathological aggregation and accumulation of tau. During the disease, tau undergoes conformational changes leading to the formation of different types of aggregates and inclusions including the widely-known neurofibrillary tangles (NFTs).

Recent findings suggest that the smaller and soluble tau oligomers are the most toxic species with more proficient seeding properties for the propagation of tau pathology as compared to the fibrillar tau [1, 2]. However, the structural and biological features of tau oligomers are still poorly understood due to their dynamic nature and conformational heterogeneity. Therefore, tau oligomers can be present in many conformations known as tau oligomeric strains. [3, 4] In preclinical studies tau aggregates have been effectively targeted by immunotherapeutic approaches, aptamers and anti-sense oligonucleotides (ASO). The focus should be on finding small molecules able to convert toxic aggregates to less toxic structures or ones that can be more easily degraded by active cellular mechanisms. Recently, we have shown that Azure C and fully synthetic heparin oligosaccharides target and modulate the aggregation states of toxic tau oligomers, resulting in the formation of larger non-toxic tau structures thus preventing the spread of the pathology. [5-7] To expand these findings, we used newly synthesized curcumin derivatives to modulate the aggregation of disease-relevant tau oligomeric strains thus to reduce their associated neurotoxicity. We performed biochemical and biophysical techniques, including direct ELISA , Western Blot analyses and AFM as well as cytotoxicity and internalization screens to characterize brain-derived tau oligomeric strains (BDTOs), isolated from different tauopathies, in the absence and presence of curcumin derivatives. Interestingly, our data suggest that newly synthesized curcumin derivatives modulate the aggregation state of BDT Os, resulting in the formation of tau species with decreased toxicity as assessed in human neuroblastoma SH-SY5Y cell and in primary cortical neurons. These results provide novel insights into tau aggregation and may lead to the discovery of new compounds effective against one or more tau strains. Finally, identification of such active compounds may lay the groundwork for developing novel therapeutic agents for AD and other tauopathies as well as advancing in diagnostic field for the detection of toxic tau oligomers and differential diagnosis for tauopathies.

References

1. Gerson, J.E. and R. Kayed, Formation and propagation of tau oligomeric seeds. Front Neurol, 2013. 4: p. 93.

2. Lasagna-Reeves, C.A., et al., Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J , 2012.

3. Sengupta, U., M. Carretero-Murillo, and R. Kayed, Preparation and Characterization of Tau Oligomer Strains. Methods Mol Biol, 2018. 1779: p. 113-146.

4. Gerson, J.E., A. Mudher, and R. Kayed, Potential mechanisms and implications for the formation of tau oligomeric strains. Crit. Rev. Biochem. Mol. Biol., 2016. 51: p. 482-496.

5. Lo Cascio, F. and R. Kayed, Azure C Targets and Modulates Toxic Tau Oligomers. 2018. 9(6): p. 1317-1326.

6. Wang, P., et al., Binding and neurotoxicity mitigation of toxic tau oligomers by synthetic heparin like oligosaccharides. Chem Commun (Camb), 2018. 54(72): p. 10120-10123.

7. Gerson, J.E., F.L. Cascio, and R. Kayed, Chapter 6 – The Potential of Small Molecules in Preventing Tau Oligomer Formation and Toxicity, in Neuroprotection in Alzheimer’s Disease, I. Gozes, Editor. 2017, Academic Press. p. 97-121.

This talk is part of the Biophysical Seminars series.

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