In the March 17 Science Signaling, researchers led by Yong-Keun Jung at Seoul National University, South Korea, reported a new modulator of γ-secretase that appears to preferentially affect cleavage of amyloid precursor protein. Stress-associated ER protein 1 (SERP1) promotes γ-secretase activity and Aβ generation, the authors claim. Intriguingly, cells activate SERP1 under conditions of cellular stress such as high glucose levels. In diabetic mice, knockdown of SERP1 lowered Aβ. “These data provide insight into a mechanism for selectively inhibiting γ-secretase to modulate Aβ production,” Jung wrote to Alzforum.
- ER protein SERP1 boosts γ-secretase activity and Aβ production.
- Conversely, it lowers Notch cleavage.
- SERP1 expression rises in diabetics, helping explain their risk for AD.
Lucía Chávez-Gutiérrez at VIB-KU Leuven Center for Brain and Disease Research, Belgium, said the findings may have relevance for Alzheimer’s disease. “The paper … highlights a potential pathogenic role for SERP1-mediated upregulation of Aβ production in diabetes and in Alzheimer’s disease,” she wrote to Alzforum (full comment below). Scientists were more skeptical about whether the findings offer a therapeutic target (see comments by Weiming Xia and Grace Stutzmann below).
Researchers have attempted to find physiological modulators of the γ-secretase complex before, proposing candidates such as β-arrestin 2 and G-protein coupled receptor 3 (Gpr3) (Dec 2012 news; Oct 2015 news). One high-profile putative modulator, γ-secretase activating protein (GSAP), did not replicate in subsequent studies (Sep 2010 news; Jan 2014 news).
To find other physiological modulators of γ-secretase, Jung and colleagues previously ran a gain-of-function screen in HEK 293 cells, looking for genes that affected the enzyme’s activity (Han et al., 2014). This turned up SERP1, a single-pass transmembrane protein of 64 amino acids that stimulated γ-secretase. SERP1 sits in the ER membrane and is activated by ER stress (Yamaguchi et al., 1999; Lee et al., 2003).
In the new study, joint first authors Sunmin Jung and Junho Hyun delved into mechanism. They confirmed that, in two different cultured cell lines expressing mutant APP, overexpressing SERP1 bumped up secreted Aβ by as much as 70 percent, while knocking down SERP1 suppressed Aβ. Crucially, however, SERP1 had milder and opposite effects on Notch. SERP1 overexpression lessened Notch cleavage by 30 percent, and knockdown had no effect. SERP1 appears to be a negative regulator of Notch cleavage, the authors noted.
Further experiments elucidated what lay behind these observations. The effect hinged on the makeup of the γ-secretase complex. The mature complex comprises four subunits: presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective phenotype 1. APH1 itself comes in three isoforms, A, B, and C. SERP1 stabilized the binding of nicastrin to the APH1A isoform, thus boosting the amount of mature γ-secretase. Notably, APH1A isoform was previously implicated in pumping up amyloidogenic processing of APP (May 2009 news).
Co-immunoprecipitation showed that SERP1 directly interacted with both APH1 and nicastrin. SERP1 also increased the amount of γ-secretase found in lipid rafts, where APP gets cleaved (see image above). Notch is cleaved elsewhere, suggesting one mechanism for substrate selectivity (Vetrivel et al., 2005).
Chávez-Gutiérrez considers these interaction data convincing. Weiming Xia at Boston University agreed. “They did an excellent job in dissecting the molecular architecture of SERP1 and APH1A/Nicastrin,” he wrote to Alzforum (full comment below).
How would ER stress alter the picture? In cultures, the authors stressed cells by inhibiting the ER calcium channel SERCA. This increased SERP1 expression and Aβ production. When the authors knocked down SERP1 before applying the channel blocker, Aβ levels did not change, confirming that SERP1 was crucial to this response. The stress response was mediated by the ER stress sensor inositol-requiring enzyme 1. Blocking IREP1 prevented the increase in SERP1.
Because high blood sugar causes ER stress, the authors examined a mouse model of diabetes induced by injecting the pancreatic β cell poison streptozotocin. These mice had increased SERP1 expression and more γ-secretase complex in the brain. When the authors injected 3xTg mice with streptozotocin, Aβ production bumped up 20 percent. As in cell culture, the effect on Aβ could be prevented by knocking down SERP1.
Chávez-Gutiérrez found this telling. “The tripartite relationship between glucose-triggered ER stress, SERP1 levels and Aβ production may explain the link between diabetes and AD,” she wrote.
Is there evidence that SERP1 contributes to AD? The authors examined postmortem AD and control brains. In AD brain, SERP1 was up about 10-fold in hippocampal tissue, and fivefold in parietal lobe.
Because of SERP1’s selective effect on APP cleavage, the authors believe it could be a therapeutic target. They will look for inhibitors that disrupt the interaction between SERP1 and γ-secretase, Jung wrote to Alzforum. On that point, Xia cautioned that SERP1 knockout mice have poor glucose tolerance and increased ER stress. He believes more might be gained by revisiting previously identified γ-secretase modulators, evaluating their effects in animal and human studies using newly developed plasma biomarkers of amyloid, tau, and neurodegeneration. Likewise, Stutzman noted that it may be premature to begin thinking of harnessing this pathway for a therapeutic strategy, in part because SERP1 affected Aβ40 and Aβ42 in equal measure.—Madolyn Bowman Rogers
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Research Models Citations
- Han J, Jung S, Jang J, Kam TI, Choi H, Kim BJ, Nah J, Jo DG, Nakagawa T, Nishimura M, Jung YK. OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin. Cell Mol Life Sci. 2014 Jul;71(13):2561-76. Epub 2013 Nov 24 PubMed.
- Yamaguchi A, Hori O, Stern DM, Hartmann E, Ogawa S, Tohyama M. Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylation. J Cell Biol. 1999 Dec 13;147(6):1195-204. PubMed.
- Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003 Nov;23(21):7448-59. PubMed.
- Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia SS, Thinakaran G. Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem. 2005 Jul 8;280(27):25892-900. PubMed.
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- Jung S, Hyun J, Nah J, Han J, Kim SH, Park J, Oh Y, Gwon Y, Moon S, Jo DG, Jung YK. SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions. Sci Signal. 2020 Mar 17;13(623) PubMed.