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[P2–061]: DECIPHERING ROLE OF CHAMELEON SEQUENCE FRAGMENTS IN UNDERSTANDING FOLDING AND OLIGOMERIZATION OF β‐AMYLOID PEPTIDE
Author(s) -
Iqbal Saleem
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.2017.06.710
Subject(s) - peptide , p3 peptide , pentapeptide repeat , amyloid (mycology) , folding (dsp implementation) , sequence (biology) , peptide sequence , protein folding , chemistry , biochemistry of alzheimer's disease , conformational change , biochemistry , biophysics , amyloid precursor protein , biology , alzheimer's disease , medicine , disease , pathology , gene , inorganic chemistry , electrical engineering , engineering
highly specific <25mM concentration. 2-PMAP does not alter APP mRNA level, while its dose-dependent effect on APP translation was directly showed in pulse-chase studies, which also confirmed absence of 2-PMAP effect on APPmaturation, processing, and degradation. 2-PMAPhasnoeffect onAPPcleavage as shownusing specific functional assays of APP secretases. 2-PMAP is BBB penetrant after oral and intravenous dosing and when given systemically to APPSW/ PS1dE9 AD transgenic mice it reduced levels of full length APP, APP C-terminal fragments (CTFs) and levels of soluble Abx-40 and Abx-42 in the brain. A chronic, four-month treatment of APPSW/ PS1dE9micewith 2-PMAP produced significant reduction inAb brain deposition and did not reveal any evidence of observable toxicity, while rescuing the mice from memory deficit. Conclusions: 2-PMAP is a small molecule therapeutic effectively ameliorating Ab pathology through targeting APP translation. 2-PMAP is unlikely to evoke off target effects associated with APP secretases inhibition and provides additional benefit in lowering levels of cytotoxic APP CTFs.