Premium
[P1–278]: AGE‐WEIGHTED POLYGENIC RISK MODEL EFFECTIVELY PREDICTS THE ONSET OF ALZHEIMER DISEASE
Author(s) -
Lee Jang Jae,
Kang Sarang,
Lee Wooje,
Gunasekaran Tamil Iniyan,
Park Jung Eun,
Seo Hyeonjeong,
Park Mihye,
Rhee Sangmyung,
Kim Hoowon,
Kim Byeong Chae,
Choo IL Han,
Ikeuchi Takeshi,
Choi Kyu Yeong,
Lee Kun Ho
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.294
Subject(s) - logistic regression , genome wide association study , single nucleotide polymorphism , proportional hazards model , disease , regression , medicine , biology , statistics , genetics , genotype , gene , mathematics
addressed this problem by developing a technology to reproducibly generate stable soluble Aß1-42 oligomers that are devoid of monomeric or fibrillar Aß and show biophysical properties indistinguishable from the native species. Furthermore, Crossbeta oligomers demonstrate typical functionality of pathological Ab species such as neurotoxicity, in vivo LTP depression and induction of inflammatory response. The availability of the stable oligomers opens previously inaccessible avenues for R&D. For example, it enabled high throughput screening of drug-like compound libraries. Derived from a 100k compound screening effort, small molecule CBB68 was identified and shown to neutralize oligomer-induced neurotoxicity in rat primary neurons and to rescue the synaptic deficit induced by Ab oligomers in vivo as well as in vitro. In particular, the in vivo LTP assay demonstrated the efficacy and brain penetration of CBB68 after intravenous administration. In another application, Crossbeta’s oligomers have also been used to select shark antibodies that specifically recognize a conformational oligomeric epitope and bind to Aß142 oligomers with high affinity (sub-nM), but not to the monomers or fibrils. This antibody provides potential to selectively quantify Aß1-42 oligomers in patient material as part of a high sensitivity biomarker assay together with the stable Crossbeta oligomers as calibrator. Furthermore, the oligomers are excellent research tools, e.g. in disease-relevant bioassays. We show and conclude that the stable oligomers enable multiple applications and constitute optimum drug targets.