. SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions. Sci Signal. 2020 Mar 17;13(623) PubMed.


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  1. Jung et al. have discovered SERP1, a facilitator for the assembly of the γ-secretase complex and the generation of amyloid β protein (Aβ). They did an excellent job in dissecting the molecular architecture of SRRP1-APH1A/Nicastrin, and provided detailed in vitro and in vivo evidence to support its role in γ-secretase cleavage of APP and Notch. The question is, is SERP1 a target for AD therapeutic development?

    Unfortunately, the SERP1 knockout mice carry too many problems. As the authors point out, the SERP1 KO mice have impaired glucose tolerance. Pancreatic islets from SERP1 KO mice showed a significant delay of insulin synthesis/secretion after glucose challenge (Hori et al., 2006). Knocking out SERP1 enhances ER stress and suppresses protein translation, which could contribute to growth retardation and increased mortality. Jung's group discovered this potential target but faces a daunting challenge in validating this target for AD drug development.

    There are a number of high-profile γ-secretase modulating factors, like SERP1, that have been discovered and explored as AD therapeutic targets in the past 15 years. They include TMP21, G protein-coupled receptor 3, and β-arrestin 1. The lack of progress in therapeutic development based on these modulators could be due to the failure of several clinical trials of γ-secretase inhibitors. At the time of stopping the clinical trial of the γ-secretase inhibitor semagacestat nine years ago, non-selective inhibition of Notch cleavage by the γ-secretase was considered as the primary reason for the failure. In this regard, targeting SERP1 would avoid this problem and reduce Aβ production without affecting Notch signaling.

    With recent advances in plasma biomarker discoveries, the AT(N) system (Amyloid deposition, Tau pathology, and Neurodegeneration) could be efficiently and economically utilized to screen preclinical AD subjects for trial enrollment. Since targeting secretases (β- and γ-secretases) acts upstream of AD pathological change, manipulating modulators like SERP1 will readily illustrate changes of AT(N) biomarkers in animal and human studies. It is time to revisit these modulators and determine their efficacies in the context of AT(N) biomarkers, with the ultimate goal of preventing neurodegeneration.


    . Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum (ER) translocation sites, leads to ER stress. Mol Cell Biol. 2006 Jun;26(11):4257-67. PubMed.

    View all comments by Weiming Xia
  2. These findings about SERP1 are interesting from a cell biology/protein handling perspective, and they introduce novel ways of thinking about how cellular metabolism and stress can influence protein handling and signaling cascades. The authors present a compelling mechanism by which SERP1 function is altered to preferentially drive γ-secretase cleavage of APP and increase Aβ peptides under ER stress conditions.

    That said, I think it's premature to begin thinking of harnessing this pathway for a therapeutic strategy. Reasons include the apparently equal effects on Aβ40 and 42 peptides, or at least their suppression by shSERP1, which is inconsistent with the preferential increase of the more pathogenic Aβ42 species in AD and the increase in Aβ42:40 ratios in the 3xTg mice. Other than Figure 6 (panel 6b and c), there is no analysis of Aβ40 or 42 levels, so it is unclear how to link this to amyloidopathy.  Also, reducing Aβ40 may introduce undesirable effects as this peptide is associated with physiological functions as well. Thus, reducing SERP1 levels or function lacks the required specificity to target specific Aβ peptides associated with proteinopathy. 

    On a broader scale, it remains increasingly unclear how, or if, reducing amyloid levels in the brain may improve cognitive function or overall outcomes in AD patients. Based on the long list of failures in this domain, this variation of a theme doesn't seem sufficiently different to offer convincing hope for this approach.

    View all comments by Grace Stutzmann
  3. This paper presents SERP1 as a direct modulator of γ-secretase activity under ER stress, and highlights a potential pathogenic role for the SERP1-mediated upregulation of Aβ production in diabetes and in Alzheimer’s disease (AD).

    The authors convincingly demonstrate that the modulatory effect is mediated by a direct interaction of SERP1 with the NCT-APH subcomplex that increases its levels, as well as the steady-state levels of the γ-secretase complex. SERP1 not only enhances γ-secretase complex levels, but also localizes its activity to lipid rafts. Thus, this effect has further implications for the γ-secretase processing of substrates, as it favors the cleavage of substrates co-localizing with the protease in rafts (APP) over substrates with a non-lipid raft localization (e.g., Notch).

    Since ER stress regulates SERP1expression levels, the authors investigated whether ER stress has an effect on γ-secretase activity and consequently Aβ production. Interestingly, the report shows that under hyperglycemia-triggered ER stress, increased SERP1 levels result in elevated γ-secretase steady-state levels and higher Aβ production. The tripartite relationship between glucose-triggered ER stress, SERP1 levels, and  Aβ production may explain the link between diabetes and AD.

    Intriguingly, the authors found increased abundance of SERP1 (~9.6-fold) in postmortem hippocampal AD brain tissue, relative to age-matched, non-AD samples. Of note, Hata et al. recently reported increased γ-secretase activity in detergent-resistant fractions (lipid rafts) prepared from postmortem AD brain samples, relative to controls.

    Collectively, these observations support the contribution of γ-secretase activity/increased Aβ production to sporadic AD.


    . Enhanced amyloid-β generation by γ-secretase complex in DRM microdomains with reduced cholesterol levels. Hum Mol Genet. 2020 Feb 1;29(3):382-393. PubMed.

    View all comments by Lucia Chavez-Gutierrez

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  1. Stress-Associated Protein Modulates γ-Secretase to Make More Aβ