b-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 b-amyloid (Ab) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Ab 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.

A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis / G. Di Fede, M. Catania, M. Morbin, G. Rossi, S. Suardi, G. Mazzoleni, M. Merlin, A.R. Giovagnoli, S. Prioni, A. Erbetta, C. Falcone, M. Gobbi, L. Colombo, A. Bastone, M. Beeg, C. Manzoni, B. Francescucci, A. Spagnoli, L.F. Cantu’, E. Del Favero, E. Levy, M. Salmona, F. Tagliavini. - In: SCIENCE. - ISSN 0036-8075. - 323:5920(2009), pp. 1473-1477. [10.1126/science.1168979]

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

L.F. Cantu’;E. Del Favero;
2009

Abstract

b-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 b-amyloid (Ab) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Ab 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.
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
2009
Article (author)
File in questo prodotto:
File Dimensione Formato  
nihms-111340_versione_autore.pdf

accesso aperto

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 1.67 MB
Formato Adobe PDF
1.67 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/143345
Citazioni
  • ???jsp.display-item.citation.pmc??? 149
  • Scopus 327
  • ???jsp.display-item.citation.isi??? 315
social impact