Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β 2 generation

Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, Md Shahaduzzaman, Yuyuan Zhu, Takashi Mori, Mark P. Mattson, Jun Tan

Research output: Contribution to journalArticlepeer-review

Abstract

In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-β (Aβ) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aβ generation by directly associating with β-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aβ production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases β-amyloid plaques and soluble A 2. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aβ-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.

Original languageEnglish (US)
Article number1781
JournalNature Communications
Volume3
DOIs
StatePublished - 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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