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SUMMARY:Modulating Disease-relevant Tau Oligomeric Strains by Small Molecu
 les - Filippa Lo Cascio\, University of Texas Medical Branch
DTSTART:20190321T103000Z
DTEND:20190321T113000Z
UID:TALK121489@talks.cam.ac.uk
CONTACT:Gabriella Heller
DESCRIPTION:Alzheimer’s diseases (AD) is the most common age-related neu
 rodegenerative 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\, ta
 u undergoes conformational changes leading to the formation of different t
 ypes of aggregates and inclusions including the widely-known neurofibrilla
 ry tangles (NFTs). \n\nRecent findings suggest that the smaller and solubl
 e tau oligomers are the most toxic species with more proficient seeding pr
 operties for the propagation of tau pathology as compared to the fibrillar
  tau [1\, 2]. However\, the structural and biological features of tau olig
 omers are still poorly understood due to their dynamic nature and conforma
 tional heterogeneity. Therefore\, tau oligomers can be present in many con
 formations known as tau oligomeric strains. [3\, 4] \nIn preclinical studi
 es tau aggregates have been effectively targeted by immunotherapeutic appr
 oaches\, aptamers and anti-sense oligonucleotides (ASO). The focus should 
 be on finding small molecules able to convert toxic aggregates to less tox
 ic structures or ones that can be more easily degraded by active cellular 
 mechanisms. Recently\, we have shown that Azure C and fully synthetic hepa
 rin oligosaccharides target and modulate the aggregation states of toxic t
 au oligomers\, resulting in the formation of larger non-toxic tau structur
 es thus preventing the spread of the pathology. [5-7] To expand these find
 ings\, we used newly synthesized curcumin derivatives to modulate the aggr
 egation of disease-relevant tau oligomeric strains thus to reduce their as
 sociated neurotoxicity. We performed biochemical and biophysical technique
 s\, including direct ELISA\, Western Blot analyses and AFM as well as cyto
 toxicity and internalization screens to characterize brain-derived tau oli
 gomeric strains (BDTOs)\, isolated from different tauopathies\, in the abs
 ence and presence of curcumin derivatives. Interestingly\, our data sugges
 t that newly synthesized curcumin derivatives modulate the aggregation sta
 te of BDTOs\, resulting in the formation of tau species with decreased tox
 icity as assessed in human neuroblastoma SH-SY5Y cell and in primary corti
 cal neurons. \nThese results provide novel insights into tau aggregation a
 nd may lead to the discovery of new compounds effective against one or mor
 e tau strains. Finally\, identification of such active compounds may lay t
 he groundwork for developing novel therapeutic agents for AD and other tau
 opathies as well as advancing in diagnostic field for the detection of tox
 ic tau oligomers and differential diagnosis for tauopathies. \n\nReference
 s\n\n1.	Gerson\, J.E. and R. Kayed\, Formation and propagation of tau olig
 omeric seeds. Front Neurol\, 2013. 4: p. 93.\n\n2.	Lasagna-Reeves\, C.A.\,
  et al.\, Identification of oligomers at early stages of tau aggregation i
 n Alzheimer's disease. FASEB J\, 2012.\n\n3.	Sengupta\, U.\, M. Carretero-
 Murillo\, and R. Kayed\, Preparation and Characterization of Tau Oligomer 
 Strains. Methods Mol Biol\, 2018. 1779: p. 113-146.\n\n4.	Gerson\, J.E.\, 
 A. Mudher\, and R. Kayed\, Potential mechanisms and implications for the f
 ormation of tau oligomeric strains. Crit. Rev. Biochem. Mol. Biol.\, 2016.
  51: p. 482-496.\n\n5.	Lo Cascio\, F. and R. Kayed\, Azure C Targets and M
 odulates Toxic Tau Oligomers. 2018. 9(6): p. 1317-1326.\n\n6.	Wang\, P.\, 
 et al.\, Binding and neurotoxicity mitigation of toxic tau oligomers by sy
 nthetic heparin like oligosaccharides. Chem Commun (Camb)\, 2018. 54(72): 
 p. 10120-10123.\n\n7.	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\, Edi
 tor. 2017\, Academic Press. p. 97-121.\n
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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