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. Mufson

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 astro-cytes 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 Aβ 1-40 and Aβ 1-42, Aβ oligomers, BACE1 and GFAP levels between groups. Interestingly, the number of the hippocampal APP/Aβ plaques in female and male dime-bon-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.

Original languageEnglish (US)
Pages (from-to)115-127
Number of pages13
JournalInternational Journal of Physiology, Pathophysiology and Pharmacology
Volume4
Issue number3
StatePublished - Oct 9 2012

Keywords

  • Alzheimer's disease
  • Amyloid
  • Dimebon
  • Hippocampus
  • Plaques
  • Tangles
  • Tau
  • Transgenic mice

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Physiology
  • Physiology (medical)

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