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?-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing.

ABSTRACT: Familial mutations in C99 can increase the total level of the soluble A? peptides produced by proteolysis, as well as the A?42/A?40 ratio, both of which are linked to the progression of Alzheimer's disease. We show that the extracellular sequence of C99 forms ?-sheet structure upon interaction with membrane bilayers. Mutations that disrupt this structure result in a significant increase in A? production and, in specific cases, result in an increase in the amount of A?42 relative to A?40. Fourier transform infrared and solid-state NMR spectroscopic studies reveal a central ?-hairpin within the extracellular sequence comprising Y10-E11-V12 and L17-V18-F19 connected by a loop involving H13-H14-Q15. These results suggest how familial mutations in the extracellular sequence influence C99 processing and provide a structural basis for the development of small molecule modulators that would reduce A? production.

SUBMITTER: Hu Y

PROVIDER: S-EPMC5719365 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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β-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing.

Hu Yi Y Kienlen-Campard Pascal P Tang Tzu-Chun TC Perrin Florian F Opsomer Rémi R Decock Marie M Pan Xiaoshu X Octave Jean-Noel JN Constantinescu Stefan N SN Smith Steven O SO

Scientific reports 20171207 1

Familial mutations in C99 can increase the total level of the soluble Aβ peptides produced by proteolysis, as well as the Aβ42/Aβ40 ratio, both of which are linked to the progression of Alzheimer's disease. We show that the extracellular sequence of C99 forms β-sheet structure upon interaction with membrane bilayers. Mutations that disrupt this structure result in a significant increase in Aβ production and, in specific cases, result in an increase in the amount of Aβ42 relative to Aβ40. Fourier ...[more]

PMID: 29215043

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Project description:Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-β (Aβ), released by sequential proteolytic processing of the amyloid precursor protein (APP) by β - and γ-secretase. Aβ peptides can aggregate, leading to toxic Aβ oligomers and amyloid plaque formation. Aβ accumulation is not only dependent on de novo synthesis but also on Aβ degradation. Neprilysin (NEP) is one of the major enzymes involved in Aβ degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aβ-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the treatment of AD.

Dataset Information

?-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing.

Publications

β-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing.

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