Journal Article

<b>Nonfibrillar diffuse amyloid deposition due to a </b>γ <b><sub>42</sub></b><b>‐secretase site mutation points to an essential role for N‐truncated A</b>β<b><sub>42</sub></b><b> in Alzheimer’s disease</b>

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 and Christine Van Broeckhoven

in Human Molecular Genetics

Volume 9, issue 18, pages 2589-2598
Published in print November 2000 | ISSN: 0964-6906
Published online November 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.18.2589
Nonfibrillar diffuse amyloid deposition due to a γ
42‐secretase site mutation points to an
essential role for N‐truncated Aβ42 in
Alzheimer’s
disease

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Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid β-peptide (Aβ42) is considered central to Alzheimer’s disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid Aβ42 deposits have to mature in the presence of Aβ40 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 involvingγ -secretase cleavages of APP. The mutation had the most drastic effect on Aβ42/Aβ40 ratio in vitro of∼ 11-fold, simultaneously increasing Aβ42 and decreasing Aβ40 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 Aβ42 in complete absence of Aβ40. These data indicate that N-truncated Aβ42 as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length Aβ42 by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated Aβ42.

Journal Article.  6869 words.  Illustrated.

Subjects: Genetics and Genomics

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