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GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42.

ABSTRACT: Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases leads to the generation of amyloid-beta (Abeta) peptides with varying lengths. Particularly Abeta42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease (AD). However, the precise molecular mechanism of Abeta42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Abeta species produced. In a neuronal cell system, mutations of glycine residues G29 and G33 of the GxxxG motif gradually attenuate the TMS dimerization strength, specifically reduce the formation of Abeta42, leave the level of Abeta40 unaffected, but increase Abeta38 and shorter Abeta species. We show that glycine residues G29 and G33 are part of a dimerization site within the TMS, but do not impair oligomerization of the APP ectodomain. We conclude that gamma-secretase cleavages of APP are intimately linked to the dimerization strength of the substrate TMS. The results demonstrate that dimerization of APP TMS is a risk factor for AD due to facilitating Abeta42 production.

SUBMITTER: Munter LM

PROVIDER: S-EPMC1829382 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42.

Munter Lisa-Marie LM Voigt Philipp P Harmeier Anja A Kaden Daniela D Gottschalk Kay E KE Weise Christoph C Pipkorn Rüdiger R Schaefer Michael M Langosch Dieter D Multhaup Gerd G

The EMBO journal 20070301 6

Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases leads to the generation of amyloid-beta (Abeta) peptides with varying lengths. Particularly Abeta42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease (AD). However, the precise molecular mechanism of Abeta42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Abeta species produced. In a neuron ...[more]

PMID: 17332749

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Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the ?-amyloid peptide (A?), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble A? oligomers correlate with clinical symptoms associated with the disease. The A? sequence begins in the extracellular juxtamembrane region of APP and includes roughly half of the TM domain. This region contains GXXXG and GXXXA motifs, which are critical for both TM protein interactions and fibrillogenic properties of peptides derived from TM ?-helices. Glycine-to-leucine mutations of these motifs were previously shown to affect APP processing and A? production in cells. However, the detailed contribution of these motifs to APP dimerization, their relation to processing, and the conformational changes they can induce within A? species remains undefined. Here, we describe highly resistant A?42 oligomers that are produced in cellular membrane compartments. They are formed in cells by processing of the APP amyloidogenic C-terminal fragment (C99), or by direct expression of a peptide corresponding to A?42, but not to A?40. By a point-mutation approach, we demonstrate that glycine-to-leucine mutations in the G(29)XXXG(33) and G(38)XXXA(42) motifs dramatically affect the A? oligomerization process. G33 and G38 in these motifs are specifically involved in A? oligomerization; the G33L mutation strongly promotes oligomerization, while G38L blocks it with a dominant effect on G33 residue modification. Finally, we report that the secreted A?42 oligomers display pathological properties consistent with their suggested role in AD, but do not induce toxicity in survival assays with neuronal cells. Exposure of neurons to these A?42 oligomers dramatically affects neuronal differentiation and, consequently, neuronal network maturation.

Dataset Information

GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42.

Publications

GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42.

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