Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-? precursor protein dimerization

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dc.contributor.authorSo, Pauline P.L.
dc.contributor.authorZeldich, Ella
dc.contributor.authorSeyb, Kathleen I.
dc.contributor.authorHuang, Mickey M.
dc.contributor.authorConcannon, John B.
dc.contributor.authorKing, Gwendalyn D.
dc.contributor.authorChen, CiDi
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorGlicksman, Marcie A.
dc.contributor.authorAbraham, Carmela R.
dc.date.accessioned2020-03-10T17:31:22Z
dc.date.available2020-03-10T17:31:22Z
dc.date.issued2012-04
dc.description.abstractThe amyloid ? precursor protein (APP) is a single-pass transmembrane glycoprotein that is ubiquitously expressed in many cell types, including neurons. Amyloidogenic processing of APP by ?- and ?-secretases leads to the production of amyloid-? (A?) peptides that can oligomerize and aggregate into amyloid plaques, a characteristic hallmark of Alzheimer’s disease (AD) brains. Multiple reports suggest that dimerization of APP may play a role in A? production; however, it is not yet clear whether APP dimers increase or decrease A? and the mechanism is not fully understood. To better understand the relationship between APP dimerization and production of A?, a high throughput screen for small molecule modulators of APP dimerization was conducted using APP-Firefly luciferase enzyme complementation to detect APP dimerization. Selected modulators identified from a compound library of 77,440 compounds were tested for their effects on A? generation. Two molecules that inhibited APP dimerization produced a reduction in A? levels as measured by ELISA. The inhibitors did not change sAPP? or ?-CTF levels, but lowered sAPP? levels, suggesting that blocking the dimerization is preventing the cleavage by ?-secretase in the amyloidogenic processing of APP. To our knowledge, this is the first High Throughput Screen (HTS) effort to identify small molecule modulators of APP dimerization. Inhibition of APP dimerization has previously been suggested as a therapeutic target in AD. The findings reported here further support that modulation of APP dimerization may be a viable means of reducing the production of A?.
dc.identifier.citationCopyright 2012 American Journal of Neurodegenerative disease. Recommended citation: So, Pauline PL, Ella Zeldich, Kathleen I. Seyb, Mickey M. Huang, John B. Concannon, Gwendalyn D. King, Ci-Di Chen, Gregory D. Cuny, Marcie A. Glicksman, and Carmela R. Abraham. "Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-? precursor protein dimerization." American journal of neurodegenerative disease 1, no. 1 (2012): 75. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560454/. Reproduced in accordance with the original publisher's licensing terms and with permission from the authors.
dc.identifier.urihttps://hdl.handle.net/10657/5950
dc.language.isoen_US
dc.publisherAmerican Journal of Neurodegenerative disease
dc.subjectAlzheimer disease
dc.subjectamyloid-B precursor protein
dc.subjectprotein dimerization
dc.subjectamyloid beta-peptides
dc.subjecthigh-throughput screening
dc.subjectfirefly luciferase complementation
dc.titleLowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-? precursor protein dimerization
dc.typeArticle

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