Journal
NATURE COMMUNICATIONS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1781
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Funding
- NIH/NIA [R01AG032432, R42AG031586]
- National Institute on Aging
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Medical Research Service
- Grants-in-Aid for Scientific Research [22500320] Funding Source: KAKEN
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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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