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Science 13 March 2009:
Vol. 323. no. 5920, pp. 1473 - 1477
DOI: 10.1126/science.1168979
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Reports

A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis

Giuseppe Di Fede,1 Marcella Catania,1 Michela Morbin,1 Giacomina Rossi,1 Silvia Suardi,1 Giulia Mazzoleni,1 Marco Merlin,1 Anna Rita Giovagnoli,1 Sara Prioni,1 Alessandra Erbetta,2 Chiara Falcone,3 Marco Gobbi,4 Laura Colombo,4 Antonio Bastone,4 Marten Beeg,4 Claudia Manzoni,4 Bruna Francescucci,5 Alberto Spagnoli,5 Laura Cantù,6 Elena Del Favero,6 Efrat Levy,7 Mario Salmona,4 Fabrizio Tagliavini1*

β-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.

1 Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
2 Division of Neuroradiology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
3 Division of Neuroepidemiology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
4 Department of Molecular Biochemistry and Pharmachology, Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
5 Division of Cognitive Disorders, Centro Sant'Ambrogio Fatebenefratelli, Cernusco sul Naviglio, 20063 Milan, Italy.
6 Department of Medical Chemistry, Biochemistry, and Biotechnology, University of Milan, Segrate, 20090 Milan, Italy.
7 Departments of Pharmacology and Psychiatry, New York University School of Medicine, and Nathan S. Kline Institute, Orangeburg, NY 10962, USA.

* To whom correspondence should be addressed. E-mail: ftagliavini{at}istituto-besta.it

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Science. ISSN 0036-8075 (print), 1095-9203 (online)