Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer's disease
Open Access
- 1 November 2000
- journal article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 9 (18) , 2589-2598
- https://doi.org/10.1093/hmg/9.18.2589
Abstract
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.Keywords
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