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

被引:144
作者
Obregon, Demian [1 ,2 ]
Hou, Huayan [1 ]
Deng, Juan [1 ]
Giunta, Brian [1 ,3 ]
Tian, Jun [1 ]
Darlington, Donna [1 ]
Shahaduzzaman, Md [1 ,4 ]
Zhu, Yuyuan [1 ]
Mori, Takashi [5 ,6 ,7 ]
Mattson, Mark P. [8 ]
Tan, Jun [1 ,2 ]
机构
[1] Univ S Florida, Rashid Lab Dev Neurobiol, Silver Child Dev Ctr, Dept Psychiat & Behav Neurosci,Morsani Coll Med, Tampa, FL 33613 USA
[2] James A Haley Vet Hosp, Tampa, FL 33612 USA
[3] Univ S Florida, Dept Psychiat & Behav Neurosci, Morsani Coll Med, Neuroimmunol Lab, Tampa, FL 33613 USA
[4] Univ S Florida, Ctr Aging & Brain Repair, Morsani Coll Med, Dept Neurosurg & Brain Repair, Tampa, FL 33613 USA
[5] Saitama Med Ctr, Dept Biomed Sci, Kawagoe, Saitama 3508550, Japan
[6] Saitama Med Ctr, Dept Pathol, Kawagoe, Saitama 3508550, Japan
[7] Saitama Med Univ, Kawagoe, Saitama 3508550, Japan
[8] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA
关键词
ALZHEIMERS-DISEASE; GAMMA-SECRETASE; OXIDATIVE STRESS; CLEAVING ENZYME; A-BETA; BACE1; APP; CLEAVAGE; SITE; EXPRESSION;
D O I
10.1038/ncomms1781
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-beta (A beta) peptides accumulate. Here we show that soluble amyloid precursor protein-alpha (sAPP-alpha) decreases A beta generation by directly associating with beta-site APP-converting enzyme (BACE) 1, thereby modulating APP processing. Whereas specifically targeting sAPP-alpha using antibodies enhances A beta production; in transgenic mice with AD-like pathology, sAPP-alpha overexpression decreases beta-amyloid plaques and soluble A beta. In support, immunoneutralization of sAPP-alpha 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-alpha in brains of AD patients, inadequate sAPP-alpha levels may be sufficient to polarize APP processing towards the amyloidogenic, A beta-producing route. Therefore, restoration of sAPP-alpha or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.
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页数:9
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