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BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis
Zhe Wang1,2,3, Qin Xu2, Fang Cai2
1The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.
JCI Insight
|January 11, 2019
Summary
Beta-secretase 2 (BACE2) contributes to Alzheimer's disease (AD) by cleaving amyloid precursor protein (APP). Targeting BACE2 offers a potential therapeutic strategy for AD, avoiding BACE1 inhibition side effects.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque deposition.
- Aβ is produced from amyloid precursor protein (APP) via β- and γ-secretase activity.
- BACE1 is the primary β-secretase, but its inhibition causes adverse effects.
Purpose of the Study:
- To investigate the role of BACE2 in APP processing and Alzheimer's disease pathogenesis.
- To explore BACE2 as a potential therapeutic target for AD.
Main Methods:
- Analysis of BACE2 processing of APP, including the role of the juxtamembrane helix (JH).
- Investigating the impact of JH-disrupting mutations and clusterin binding.
- Quantification of BACE2 and clusterin levels in aged mouse brains.
Main Results:
- BACE2 can process APP at the β-site, acting as a conditional β-secretase.
- APP's juxtamembrane helix (JH) normally inhibits BACE2's β-secretase activity.
- JH disruption or clusterin binding activates BACE2-mediated β-cleavage, increasing Aβ production.
- Elevated BACE2 and clusterin levels correlate with enhanced APP β-cleavage during aging in mice.
Conclusions:
- BACE2 contributes to AD pathogenesis by acting as a conditional β-secretase.
- BACE2 represents a potential therapeutic target for AD, offering an alternative to BACE1 inhibition due to its distinct side effect profile.