Targeting APP metabolism for the treatment of Alzheimer's disease

Kumar Sambamurti, John Hardy, Lorenzo M. Refolo, Debomoy K. Lahiri

Research output: Contribution to journalReview article

18 Scopus citations

Abstract

Senile plaques consisting largely of extracellular deposits of a 38-42 residue peptide, amyloid β protein (Aβ) and intraneuronal deposits of the microtubule-associated protein, tau, as neurofibrillary tangles (NFT) are defining features of Alzheimer's disease (AD). Aβ is produced after cleavage of a larger Aβ protein precursor (APP) by β-secretase to the secreted sAPPβ and cell-associated CTFβ followed by cleavage of CTFβ by γ-secretase to secreted Aβ and the cognate cytoplasmic fragment, CTFγ. Most Aβ is 40 residues long, but a small fraction is 42-43 residues in length. A currently favored hypothesis is that Aβ42 forms toxic aggregates that induce NFT formation and ultimately the neuronal dysfunction characteristic of AD. Based on this hypothesis, the popular targets for drug development are the enzymes that generate or degrade Aβ42, block Aβ aggregation or toxicity and other factors that regulate these pathways in the brain. This article examines the evidence supporting the amyloid hypothesis and alternative hypotheses based on APP metabolism. In addition, the current drug targets for modifying APP metabolism to reduce Aβ42 are discussed. We further discuss evidence that suggests that other APP fragments such as CTFγ are altered by tested familial AD mutations and their role in AD pathogenesis needs to be carefully examined. We conclude that it is important to develop drugs based on alternative APP fragments (i.e., CTFγ) as well as the other identified pathways (i.e., oxidative stress) to provide alternatives if antiamyloid drugs fail to treat AD.

Original languageEnglish (US)
Pages (from-to)211-227
Number of pages17
JournalDrug Development Research
Volume56
Issue number2
DOIs
StatePublished - Jun 1 2002

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Keywords

  • AICD
  • Alzheimer's disease
  • Amyloid peptide
  • Amyloid protein precursor
  • BACE
  • CTFγ
  • CTFε
  • NICD
  • NSAIDS
  • Site APP cleaving enzyme
  • Statins
  • β secretase

ASJC Scopus subject areas

  • Drug Discovery

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