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New Receptor for Cdk5 and Tau-mediated AD Pathology_Seoul National Univ.
Korea Health Industry Development Institute (KHIDI) South Korea flag South Korea
Abstract ID:
New receptor for cdk5 and Tau-mediated AD pathology...
Contact Yong U Kim
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1. Background of Technology


1.1. Clinical implication of Tau modification in Alzheimer’s disease


- Clinical association of Tau hyper-phosphorylation with Alzheimer’s disease


: PHF(paired helical filament) with hyper-phosphorylated tau found in AD patients and Tauopathy


: Gsk and cdk5 kinase are responsible for Tau pathologic phosphorylation


- Clinical correlation of Tau aggregation with Alzheimer’s disease


           : Tau oligomer and aggregates found in AD patients and Tauopathy


 


1.2. Newly being developed but not successful yet


- Active initiation of Tau modification/aggregation pathology research


          : Compared to amyloid, less effort has been done. But active researches increase (2008, 2009, ICAD)


- Recent initiation with High through-put screening for Tau aggregation modulator


          : Development for cdk5 Inhibitors and screening of Tau aggregation blocker (2008, 2009 ICAD)


 


1.3. Limited screening assays and a few available targets for drug development


- A few targets, including GSK3b and cdk5/p25


          : Most laboratories or Biotech Inc. are working on a few targets known in public domain for tauopathy, such as GSK3b and cdk5. There are not many targets for drug development.  


-Competitive new targets needed


             : More targets are required, including upstream of GSK or cdk5 for Tau modification and aggregation etc.


 


2. Description on Technology Applied


2.1. Unique establishment of modified-Tau cell-based assay for high contents screening


- We established Tau aggregation cell-based assay and prepared cDNA library for screening


: Most laboratories have used in vitro aggregation assays using purified Tau for compound screening because there is little available cell-based assay system. We established modified Tau-based cell assay for tau aggregation. In contrast to other genome-wide screening, we collected human cDNA in a mammalian expression vector (>17,000) for gain-of-screening (Fig. 1).


-Successful high-content screening for gain-of-function using cDNA


             : From high-content screening using cDNA (>4,000 cDNA), we successfully isolated new genes and pathways which regulate Tau aggregation and hyper-phosphorylation.


2.2. R receptor: Isolation of new pathway (genes) for Tau phosphorylation/aggregation 


- In vitro characterization: Role of R receptor in Tau hyper-phosphorylation/aggregation


          : Expression or knockdown of R receptor modulates Tau phosphorylation/aggregation in neuronal cells. In addition, R receptor affects neuronal cell’s viability.


-R receptor as an upstream of cdk5 for Tau hyper-phosphorylation/aggregation


: R receptor seems to work at an upstream of cdk5 in cell level.


- in vivo characterization for neurotoxicity, providing proof of concept


             : In fly rough eye model, R receptor increases Tau-induced neuronal degeneration, while dominant negative mutant rescues the toxic effects induced by Tau.


             (* In R receptor knockout mice, R receptor seems to be viable but looks better smart).

FEATURED
Last Updated Jun 2016
Technology Type PLATFORM
Phase of Development EARLY STAGE
GOVERNMENT INSTITUTE