Alzheimerʼs disease: mutations, apoptosis and cellular signalling

Abstract

Purpose of review Mutations in the amyloid precursor protein, presenilin 1 and presenilin 2 genes are believed to cause early onset familial Alzheimer's disease by increasing the production of more amyloidogenic forms of the β-amyloid peptide (so called Aβ42). However, the phenotypes of familial Alzheimer's disease mutations are more complex than can be explained only by effects on amyloid precursor protein processing and β-amyloid production. This review summarises alternative ideas suggesting that familial Alzheimer's disease mutations cause disease by altering cellular signalling systems to increase the vulnerability of neurons to die by apoptosis. Recent findings The themes covered by this article include the consequences of altered amyloid precursor protein and presenilin function for apoptotic signalling, as well as the neurotoxic mechanism of action of the β-amyloid peptide. We also review the recent findings implicating altered insulin/insulin growth factor I signal transduction as a recurrent feature in many of the processes considered to result in apoptotic cell death in Alzheimer's disease. Summary Insulin growth factor I has previously received much attention as a potential therapeutic agent for Alzheimer's disease due to its multiple neuroprotective and neurotrophic effects. New findings indicating that altered insulin growth factor I signalling may be involved in the mechanism of action of β-amyloid and famililal Alzheimer's disease-causing gene mutations have reawakened interest in this molecule and its signalling pathways. The identification of insulin/insulin growth factor I signalling alterations in sporadic and familial Alzheimer's disease may provide novel targets for therapies designed to slow or prevent the neurodegeneration associated with this devastating disorder.