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Human Molecular Genetics, 2000, Vol. 9, No. 18 2589-2598
© 2000 Oxford University Press

Nonfibrillar diffuse amyloid deposition due to a {gamma}42-secretase site mutation points to an essential role for N-truncated Aß42 in Alzheimer’s disease

Samir Kumar-Singh, Chris De Jonghe, Marc Cruts, Reinhold Kleinert1, Rong Wang2, Marc Mercken3, Bart De Strooper4, Hugo Vanderstichele5, Ann Löfgren, Inge Vanderhoeven, Hubert Backhovens, Eugeen Vanmechelen5, Peter M. Kroisel6 and Christine Van Broeckhoven+

Laboratory of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, Universiteitsplein 1, B-2610, Antwerpen, Belgium, 1Laboratory of Neuropathology, Institute of Pathology and 6Laboratory of Human Genetics, Institute for Medical Biology and Human Genetics, University of Graz, Austria, 2Laboratory for Mass Spectrometry, The Rockefeller University, NY, USA, 3Janssen Research Foundation, Beerse, Belgium, 4Laboratory of Neuronal Cell Biology and Gene Transfer, University of Leuven and 5Innogenetics, Zwijnaarde, Belgium

Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid ß-peptide (Aß42) is considered central to Alzheimer’s disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid Aß42 deposits have to mature in the presence of Aß40 into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving {gamma}-secretase cleavages of APP. The mutation had the most drastic effect on Aß42/Aß40 ratio in vitro of ~11-fold, simultaneously increasing Aß42 and decreasing Aß40 secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated Aß42 in complete absence of Aß40. These data indicate that N-truncated Aß42 as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length Aß42 by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated Aß42.

+ To whom correspondence should be addressed. Tel: +32 3 820 2601; Fax:+32 3 820 2541; Email: cvbroeck@uia.ua.ac.be


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