Abstract
Backgroundβ-site APP cleaving enzyme 1 (BACE1) cleaves β-amyloid precursor protein (APP) to initiate the production of β-amyloid (Aβ), the prime culprit in Alzheimer’s disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect Aβ generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/Aβ generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation.ResultsHerein, we find that SNX12 is widely expressed in brain tissues and is mainly localized in the early endosomes. Overexpression of SNX12 does not affect the steady-state levels of APP, BACE1 or γ-secretase components, but dramatically reduces the levels of Aβ, soluble APPβ and APP β-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect γ-secretase activity or in vitro β-secretase activity. Further studies reveal that SNX12 interacts with BACE1 and downregulation of SNX12 accelerates BACE1 endocytosis and decreases steady-state level of cell surface BACE1. Finally, we find that the SNX12 protein level is dramatically decreased in the brain of AD patients as compared to that of controls.ConclusionThis study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting β-processing of APP for Aβ production. The reduced level of SNX12 in AD brains suggests that an alteration of SNX12 may contribute to AD pathology. Therefore, inhibition of BACE1-mediated β-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.
Highlights
A major pathological hallmark of Alzheimer’s disease (AD) is the formation of senile plaques in the brain
To confirm the regulation of Aβ by sorting nexin 12 (SNX12) in primary neurons, we downregulated SNX12 using lentivirus infection in primary neurons derived from amyloid precursor protein (APP)/presenilin 1 (PS1)/tau triple transgenic mice [25] and found that the levels of Aβ40 and Aβ42 secreted by primary neurons were significantly increased upon downregulation of SNX12 (Figure 1C)
The results showed that SNX12 co-localized with Background: β-site APP cleaving enzyme 1 (BACE1) (Figure 5A)
Summary
A major pathological hallmark of Alzheimer’s disease (AD) is the formation of senile plaques in the brain. The major components of senile plaques are heterogeneous small peptides called β-amyloid (Aβ) [1]. Β-cleavage of APP generates a soluble APPβ (sAPPβ) fragment and a membrane-associated APP β-carboxyl terminal fragment (βCTF). Aβ peptides are derived from the β-amyloid precursor protein (APP) through sequential proteolytic cleavages; first by β-secretase and by γ-secretase. The latter can be cleaved by γ-secretase to release Aβ. The type I transmembrane aspartyl protease, β-site APP cleaving enzyme 1 (BACE1), is the putative β-secretase [5,6,7,8]. Several proteins have been found to interact with BACE1 and regulate its intracellular trafficking, such as reticulon/ Nogo [13,14,15], Golgi-localized γ-ear-containing ARFbinding (GGA) [16,17,18] and sorting nexin 6 (SNX6) [19], the detailed mechanism underlying BACE1 trafficking regulation has yet to be fully elucidated
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