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

137Citations
Citations of this article
128Readers
Mendeley users who have this article in their library.

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.

References Powered by Scopus

The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor

4221Citations
N/AReaders
Get full text

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

4037Citations
N/AReaders
Get full text

β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

3498Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Alzheimer disease models and human neuropathology: Similarities and differences

338Citations
N/AReaders
Get full text

Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer's disease

322Citations
N/AReaders
Get full text

Intraneuronal Aβ, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease

314Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Kumar-Singh, S., De Jonghe, C., Cruts, M., Kleinert, R., Wang, R., Mercken, M., … Van Broeckhoven, C. (2000). 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. Human Molecular Genetics, 9(18), 2589–2598. https://doi.org/10.1093/hmg/9.18.2589

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 45

51%

Professor / Associate Prof. 23

26%

Researcher 20

23%

Readers' Discipline

Tooltip

Agricultural and Biological Sciences 34

40%

Neuroscience 22

26%

Medicine and Dentistry 15

17%

Biochemistry, Genetics and Molecular Bi... 15

17%

Save time finding and organizing research with Mendeley

Sign up for free