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Am J Neurodegener Dis 2012;1(1):75-87

Original Article
Lowering of amyloid beta peptide production with a small molecule
inhibitor of amyloid-β precursor protein dimerization

Pauline PL So, Ella Zeldich, Kathleen I Seyb, Mickey M Huang, John B Concannon, Gwendalyn D King, Ci-Di Chen,
Gregory D Cuny, Marcie A Glicksman, Carmela R Abraham

Department of Medicine Graduate Program in Molecular Medicine and Department of Biochemistry, Boston University
School of Medicine, Boston, MA, USA; Laboratory for Drug Discovery in Neurodegeneration (LDDN), Harvard
NeuroDiscovery Center, Brigham and Woman’s Hospital, and Harvard Medical School, Boston, MA, USA.

Received April 17, 2012; accepted April 22, 2012; Epub April 23, 2012; published May 30, 2012

Abstract: The 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 beta- and gamma- secretases
leads to the production of amyloid-beta (Aβ) 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 Aβ production; however, it is not yet clear whether APP dimers increase or decrease Aβ and the mechanism is
not fully understood.  To better understand the relationship between APP dimerization and production of Abeta, 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 Abeta generation.  Two  molecules that inhibited APP dimerization
produced a reduction in Abeta levels as measured by ELISA.  The inhibitors did not change sAPPalpha or gamma-CTF
levels, but lowered sAPPbeta levels, suggesting that blocking the dimerization is preventing the cleavage by beta-
secretase in the amyloidogenic processing of APP.  To our knowledge, this is the first 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 Abeta. (AJND1104004)

Keywords: Alzheimer disease, amyloid-β precursor protein, protein dimerization, amyloid beta-peptides, high-
throughput screening, firefly luciferase complementation

Address all correspondence to:
Dr. Carmela R Abraham, PhD
Department of Biochemistry
Boston University School of Medicine
72 East Concord Street, K-304
Boston, MA, 02118, USA.
Phone: (617) 638-4308, Fax: (617) 638-5339
E-mail: cabraham@bu.edu