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Familial Alzheimer's mutations within APPTM increase A?42 production by enhancing accessibility of ?-cleavage site.

ABSTRACT: The high A?42/A?40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of A? is generated by ?-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ?-cleavage at either T48 or L49, resulting in subsequent production of A?42 or A?40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site ?-secretase for the initial ?-cleavage, and consequently shift cleavage preference towards A?42.

SUBMITTER: Chen W

PROVIDER: S-EPMC4082030 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site.

Chen Wen W Gamache Eric E Rosenman David J DJ Xie Jian J Lopez Maria M MM Li Yue-Ming YM Wang Chunyu C

Nature communications 20140101

The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) ...[more]

PMID: 24390130

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Project description:Mutations in amyloid ? precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, ?-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp1 site to generate C99 for amyloid ? protein (A?) production, and predominantly at major Glu11 site to generate C89, resulting in truncated A? production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential ?-cleavage site of BACE1 in APP from the Glu11 site to the Asp1 site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited ?-secretase cleavage of the mutant C99 to generate A?, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.SIGNIFICANCE STATEMENT ?-site APP cleaving enzyme 1 (BACE1) is essential for amyloid ? protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu11 to the Asp1 site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid ? precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited ?-secretase cleavage of the mutant C99 to generate amyloid ? protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.

Dataset Information

Familial Alzheimer's mutations within APPTM increase A?42 production by enhancing accessibility of ?-cleavage site.

Publications

Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site.

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