Targeting APP metabolism for the treatment of Alzheimer's disease

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 2002
Externally publishedYes

Fingerprint

Protein Precursors
Metabolism
Alzheimer Disease
Amyloid Precursor Protein Secretases
Neurofibrillary Tangles
Pharmaceutical Preparations
Deposits
Serum Amyloid A Protein
Oxidative stress
Microtubule-Associated Proteins
Poisons
Amyloid Plaques
Amyloid
Toxicity
Brain
Oxidative Stress
Agglomeration
Peptides
Mutation
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Targeting APP metabolism for the treatment of Alzheimer's disease. / Sambamurti, Kumar; Hardy, John; Refolo, Lorenzo M.; Lahiri, Debomoy.

In: Drug Development Research, Vol. 56, No. 2, 06.2002, p. 211-227.

Research output: Contribution to journalArticle

Sambamurti, Kumar ; Hardy, John ; Refolo, Lorenzo M. ; Lahiri, Debomoy. / Targeting APP metabolism for the treatment of Alzheimer's disease. In: Drug Development Research. 2002 ; Vol. 56, No. 2. pp. 211-227.
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