Bad gene, good gene: a recessive APP mutation can be both. New therapeutic perspective for Alzheimer’s disease based on an Abeta variant with dominant-negative effect on amyloidogenesis

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that affects about 6% of the population over 65 years and is one of the leading causes of death in the elderly. Neuropathologically AD is characterized by deposition of amyloid β (Aβ) aggregates in the brain. This event is believed to trigger a cascade of events that lead to neuronal dysfunction and degeneration. Despite substantial efforts in the development of disease-modifying treatments, all strategies faced serious hurdles in clinical application, and no effective drugs are currently available. As a result, AD has a severe impact on patients and their families-quality of life, and its economic burden is massive. AD is usually sporadic, but a small fraction of cases is familial. The familial forms show an autosomal dominant pattern of inheritance with virtually complete penetrance, and are linked to mutations in the amyloid beta (Aβ) precursor protein (APP), presenilin 1, or presenilin 2 genes. We have recently found an APP mutation at codon 673 (A673V) that causes early-onset AD only in the homozygous state while the heterozygous carriers are not affected even in advanced age (Di Fede et al., Science 2009, 323:1473-1477). In vitro studies showed that the A673V mutation, corresponding to position 2 of Aβ, shifts APP processing towards the amyloidogenic pathway and increases Aβ propensity to aggregate and form amyloid fibrils. However, co-incubation of A673V-mutated and wild-type peptides confers instability on Aβ aggregates, and inhibits amyloidogenesis and Aβ-mediated neurotoxicity, accounting for the absence of disease in the heterozygous carriers. These findings have important implications for genetic screening and the potential treatment of the disease. The objectives of this proposal are to unravel the molecular mechanisms of the opposite effects of the A673V APP mutation in the homo- or heterozygous state on amyloidogenesis, and to develop a therapeutic strategy for AD based on A673V-modified Aβ peptides or peptido-mimetic molecules. To fulfil these objectives we will follow a stepwise, integrated approach including (i) characterization of cellular and nematode models, (ii) computational chemistry and cell-free systems to identify and screen possible lead compounds, (iii) testing carriers to deliver the selected compound(s) to the brain, and (iv) in vivo assessment of lead compound. If successful, this project will have a tremendous socio-economical impact, and will be a major breakthrough in the AD field, providing important new information that will open innovative lines of investigation and opportunities for young scientists.