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• W2624778884 abstract "Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer9s disease (AD) or protecting against dementia. Under normal conditions, β-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp¹ site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu¹¹ site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu¹¹ site to the Asp¹ site both in male and female transgenic mice <i>in vivo</i> and in cell lines and primary neuronal culture derived from timed pregnant rats <i>in vitro</i>, 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 γ-secretase cleavage of the mutant C99 to generate Aβ, 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. <b>SIGNIFICANCE STATEMENT</b> β-site APP cleaving enzyme 1 (BACE1) is essential for amyloid β 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 β 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 γ-secretase cleavage of the mutant C99 to generate amyloid β protein, leading to recessively inherited Alzheimer9s 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." @default.
• W2624778884 created "2017-06-23" @default.
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• W2624778884 date "2017-06-16" @default.
• W2624778884 modified "2023-10-18" @default.
• W2624778884 title "BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis" @default.
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• W2624778884 doi "https://doi.org/10.1523/jneurosci.0340-17.2017" @default.
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