Metabolism of amyloid β peptide and pathogenesis of Alzheimer's disease -: Towards presymptomatic diagnosis, prevention and therapy

The conversion of what has been interpreted as normal brain aging to Alzheimer's disease (AD) via a transition state, i.e. mild cognitive impairment, appears to be a continuous process caused primarily by aging-dependent accumulation of amyloid beta peptide (A beta) in the brain. This notion give us a hope that, by manipulating the A beta levels in the brain, we may be able not only to prevent and cure the disease but also to partially control some very significant aspects of brain aging. A beta is constantly produced from its precursor and immediately catabolized under normal conditions, whereas dysmetabolism of A beta seems to lead to pathological deposition upon aging. We have focused our attention on elucidation of the unresolved mechanism of A beta catabolism in the brain. In this review, we describe a new approach to prevent AD development by reducing A beta burdens in aging brains through up-regulation the catabolic mechanism involving neprilysin that can degrade both monomeric and oligomeric forms of A beta. The strategy of combining presymptomatic diagnosis with preventive medicine seems to be the most pragmatic in both medical and socio-economical terms. We also introduce a novel non-invasive amyloid imaging approach using a high-power magnetic resonance imaging (MRI) for the presymptomatic diagnosis of AD. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.