IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2012;4(3):115-127

Original Article
Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice

Sylvia E Perez, Muhammad Nadeem, Katherine R Sadleir, Joanna Matras, Christy M Kelley, Scott E Counts, Robert Vassar, Elliott J

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; Department of Cell and Molecular Biology,
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Received August 28, 2012; accepted September 17, 2012; Epub September 20, 2012; Published September 30, 2012

Abstract: A double blind, placebo-controlled phase II study revealed that the antihistamine, Dimebon® (dimebolin, latrepirdine)
improved cognition in Alzheimer disease (AD) patients compared to placebo controls. However, the Phase III CONNECTION trial failed
to demonstrate significant differences between dimebon and placebo treatments. Despite the controversial therapeutic outcomes in
the treatment of AD, dimebon’s mechanism(s) of action within the brain remain unclear. In the present study, we evaluated the effects
of dimebon upon β-amyloid (Aβ), tau and astrocytes in the hippocampus of triple transgenic (3xTg-AD) mice, which develop AD-like
pathology in an age-dependent manner. At age 6.5 months, prior to the development of Aβ plaques in the hippocampus, male and
female 3xTg-AD mice, received a daily intraperitoneal injection of 0.1 % dimebon or saline for 1.5 months. At 8 months, quantitative
immunohistochemistry revealed a significant reduction in hippocampal/subicular APP/Aβ in dimebon-treated mice, whereas protein
bioassay found no change in full length APP, soluble Aβ1-40 and Aβ1-42, Aβ oligomers, BACE1 and GFAP levels between groups.
Interestingly, the number of the hippocampal APP/Aβ plaques in female and male dimebon-treated mice was higher compared to
gender-matched control mice. Dimebon did not alter hippocampal tau levels. Furthermore, dimebon protects SH-SY5Y neurons
against Aβ toxicity and promotes GFAP expression in primary mouse astrocyte cultures. Our findings demonstrate that dimebon in vivo
modifies hippocampal APP/Aβ pathology and in vitro protects against Aβ toxicity promoting cell survival and activates astrocytes.

Keywords: Alzheimer’s disease, amyloid, dimebon, hippocampus, plaques, tangles, tau, transgenic mice

Address all correspondence to:
Dr. Sylvia E Perez
Department of Neurological Sciences
Rush University Medical Center
1735 W. Harrison Street, Suite 324
Chicago, IL 60612, USA.
Tel: 312-563-3580; Fax: 312-563-3571
E-mail: Sylvia_e_perez@rush.edu