Novel drug targets based on metallobiology of Alzheimer's disease

Sanghamitra Bandyopadhyay, Xudong Huang, Debomoy K. Lahiri, Jack T. Rogers

Research output: Contribution to journalReview article

44 Scopus citations

Abstract

Importance of the field: Increased localization of Zn, Fe, Cu and Al within the senile plaques (SP) exacerbates amyloid beta (Aβ)-mediated oxidative damage, and acts as catalyst for Aβ aggregation in Alzheimer's disease (AD). Thus, disruption of aberrant metalpeptide interactions via chelation therapy holds considerable promise as a rational therapeutic strategy against Alzheimer's amyloid pathogenesis. Areas covered in this review: The complexities of metal-induced genesis of SP are reviewed. The recent advances in the molecular mechanism of action of metal chelating agents are discussed with critical assessment of their potential to become drugs. What the reader will gain: Taking into consideration the interaction of metals with the metal-responsive elements on the Alzheimer's amyloid precursor protein (APP), readers will gain understanding of several points to bear in mind when developing a screening campaign for AD-therapeutics. Take home message: A functional iron-responsive element (IRE) RNA stem loop in the 5′ untranslated region (UTR) of the APP transcript regulates neural APP translation. Desferrioxamine, clioquinol, tetrathiolmolybdate, dimercaptopropanol, VK-28, and natural antioxidants, such as curcumin and ginko biloba need critical evaluation as AD therapeutics. There is a necessity for novel screens (related to metallobiology) to identify therapeutics effective in AD.

Original languageEnglish (US)
Pages (from-to)1177-1197
Number of pages21
JournalExpert Opinion on Therapeutic Targets
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2010

Keywords

  • APP
  • Iron responsive element
  • Metal chelators
  • Screening

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Clinical Biochemistry
  • Molecular Medicine

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