Targeting APP metabolism for the treatment of Alzheimer's disease

Abstract

Senile plaques consisting largely of extracellular deposits of a 38-42 residue peptide, amyloid b protein (Ab) and intraneuronal deposits of the microtubule-associated protein, tau, as neurofibrillary tangles (NFT) are defining features of Alzheimer's disease (AD). Ab is produced after cleavage of a larger Ab protein precursor (APP) by b-secretase to the secreted sAPPb and cell-associated CTFb followed by cleavage of CTFb by g-secretase to secreted Ab and the cognate cytoplasmic fragment, CTFg. Most Ab is 40 residues long, but a small fraction is 42-43 residues in length. A currently favored hypothesis is that Ab42 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 Ab42, block Ab 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 Ab42 are discussed. We further discuss evidence that suggests that other APP fragments such as CTFg 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., CTFg) as well as the other identified pathways (i.e., oxidative stress) to provide alternatives if antiamyloid drugs fail to treat AD. Drug Dev. Res. 56:211-227, 2002. c 2002 Key words: Alzheimer's disease; amyloid peptide; amyloid protein precursor; b secretase; BACE; site APP cleaving enzyme; statins; NSAIDS; CTFg; CTFe; AICD; NICD Alzheimer's disease (AD) is a progressive senile dementia characterized by memory loss and cognitive impairment. Although AD is a leading cause of senile dementia affecting 35-45% of the population over the age of 80, it is important to note that it does not appear to be an inevitable consequence of aging [Silver et al., 2001]. AD poses a serious health problem of pandemic proportions. Currently, it is estimated that worldwide there are 40 million people affected by AD and it is predicted that by the year 2030 this number will reach in excess of 60 million. The economic ramifications of AD are very serious as well. AD is extremely costly to the patients, their families, and society as a whole, and last year an estimated $100 billon was spent in the United States on health care expenses and lost wages for AD patients and their caregivers. Further estimates predict that by 2050 $375 billion will be spent annually

Targets for AD treatment: conflicting messages from γ-secretase inhibitors

“…APP is a large type‐I, single‐pass integral membrane glycoprotein with a large N‐terminal ectodomain, a single transmembrane domain and a cytoplasmic domain of 47 aa (Hardy and Selkoe 2002; Sambamurti et al. 2002a,b, 2006).…”

“…The extremely early development of dementia and AD pathology in FAD also suggests that this pathology may be driven simply by Aβ accumulation (Hardy and Selkoe 2002; Sambamurti et al. 2002b).…”