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

102 Scopus citations


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
StatePublished - 2012
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Chemistry
  • General Physics and Astronomy


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