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

Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, Md Shahaduzzaman, Yuyuan Zhu, Takashi Mori, Mark P. Mattson and Jun Tan ()
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Demian Obregon: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Huayan Hou: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Juan Deng: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Brian Giunta: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Jun Tian: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Donna Darlington: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Md Shahaduzzaman: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Yuyuan Zhu: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Takashi Mori: Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama 350-8550, Japan.
Mark P. Mattson: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore 21224, Maryland, USA.
Jun Tan: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.

Nature Communications, 2012, vol. 3, issue 1, 1-9

Abstract: 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 Aβ. 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.

Date: 2012
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DOI: 10.1038/ncomms1781

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