Nonfibrillar diffuse amyloid deposition due to a γ 42-secretase site mutation points to an essential role for N-truncated Aβ 42 in Alzheimer's disease

Samir Kumar-Singh, Chris De Jonghe, Marc Cruts, Reinhold Kleinert, Rong Wang, Marc Mercken, Bart De Strooper, Hugo Vanderstichele, Ann Löfgren, Inge Vanderhoeven, Hubert Backhovens, Eugeen Vanmechelen, Peter M. Kroisel, Christine Van Broeckhoven

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid β-peptide (Aβ 42) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid Aβ 42 deposits have to mature in the presence of Aβ 40 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 γ-secretase cleavages of APP. The mutation had the most drastic effect on Aβ 42/Aβ 40 ration in vitro of ~ 11-fold, simultaneously increasing Aβ 42 and decreasing Aβ 40 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 Aβ(42) in complete absence of Aβ 40. These data indicate that N-truncated Aβ 42 as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length Aβ 42 by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated Aβ 42.

Original languageEnglish
Pages (from-to)2589-2598
Number of pages10
JournalHuman Molecular Genetics
Volume9
Issue number18
StatePublished - 1 Nov 2000
Externally publishedYes

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