Transient pharmacologic lowering of A production prior to deposition results in sustained reduction of amyloid plaque pathology

Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsenstein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, Barbara A. Osborne, Todd E. Golde

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Background: Alzheimers disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting A that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of A in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain A with a -secretase inhibitor (GSI) for 1-3months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M. Results: These data show that reducing A production in a 2-3M windows both initiated and discontinued before detectable A deposition has the most significant impact on A loads up to 11M after treatment discontinuation. In contrast, initiation of treatment for 3M windows from 7-10M or 12-15M shows progressively decreasing efficacy. Conclusions: These data have major implications for clinical testing of therapeutics aimed at lowering A production, indicating that; i) these therapies may have little efficacy unless tested as prophylactics or in the earliest preclinical stage of AD where there is no or minimal A accumulation and ii) lowering A production transiently during a critical pre-deposition window potentially provides long-lasting efficacy after discontinuation of the treatment.

Original languageEnglish (US)
Article number39
JournalMolecular neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - Aug 17 2012

Keywords

  • -secretase inhibition
  • A
  • APP
  • Alzheimers disease
  • Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Das, P., Verbeeck, C., Minter, L., Chakrabarty, P., Felsenstein, K., Kukar, T., Maharvi, G., Fauq, A., Osborne, B. A., & Golde, T. E. (2012). Transient pharmacologic lowering of A production prior to deposition results in sustained reduction of amyloid plaque pathology. Molecular neurodegeneration, 7(1), [39]. https://doi.org/10.1186/1750-1326-7-39