Insight γ-Secretase: Structure, Function, and Role in Alzheimer’s Disease

Mal, Suvadeep; Malik, Udita; Pal, Dilipkumar; Mishra, Abhishek

doi:10.2174/1389450121999201230203709

Cited by 6 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the light of our findings and the supporting documentations ( 16 , 39 – 41 ), we propose a model for PSEN1 to regulate tumor-immune interactions via influencing PD-L1 nuclear translocation ( Figure 3 ). In this model, the upregulated PSEN1 in colon cancer facilitates PD-L1 truncation via potential proteolytic processing, releasing its active C-terminal fragment, and then induces PD-L1 nuclear translocation through impacts on the multiple components in HDAC2-mediated deacetylation, clathrin-dependent endocytosis, vimentin-associated nucleocytoplasmic shuttling and importin family-mediated nuclear import.…”

Section: Resultssupporting

confidence: 57%

PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions

2022

Front. Immunol.

View full text Add to dashboard Cite

Presenilin 1 (PSEN1), as a catalytical core of the γ-secretase complex, plays multiple actions through mediating transmembrane domain shedding of the substrates. Unlike extensive studies performed on investigating the functions of γ-secretase substrates or the effects of γ-secretase inhibitors, our findings uncover a potential action of PSEN1 on PD-L1 alternative truncation and nuclear translocation, broadening our understanding on how the γ-secretase contributes to colon cancer development as well as suggesting a potential strategy to improve the efficacy of PD-1/PD-L1 blockade. Immunohistochemical data showed loss of PD-L1 protein expression in all the primary colon adenocarcioma (COAD) cases in the HPA collection, while PSEN1 was scored to be highly expressed, indicating their converse expression patterns (p<0.001). Meanwhile a strongly positive gene correlation was explored by TIMER2 and GEPIA (p<0.001). Up-regulated PSEN1 expression in COAD might facilitate liberating a C-terminal PD-L1 truncation via proteolytic processing. Then following an established regulatory pathway of PD-L1 nuclear translocation, we found that PSEN1 showed significant correlations with multiple components in HDAC2-mediated deacetylation, clathrin-dependent endocytosis, vimentin-associated nucleocytoplasmic shuttling and importin family-mediated nuclear import. Moreover, connections of PSEN1 to the immune response genes transactivated by nuclear PD-L1 were tested. Additionally, contributions of PSEN1 to the tumor invasiveness (p<0.05) and the tumor infiltrating cell enrichments (p<0.001) were investigated by cBioportal and the ESTIMATE algorithm. Levels of PSEN1 were negatively correlated with infiltrating CD8+ T (p<0.05) and CD4+ T helper (Th) 1 cells (p<0.001), while positively correlated with regulatory T cells (Tregs) (p<0.001) and cancer associated fibroblasts (CAFs) (p<0.001). It also displayed significant associations with diverse immune metagenes characteristic of T cell exhaustion, Tregs and CAFs, indicating possible actions in immune escape. Despite still a preliminary stage of this study, we anticipate to deciphering a novel function of PSEN1, and supporting more researchers toward the elucidations of the mechanisms linking the γ-secretase to cancers, which has yet to be fully addressed.

show abstract

Section: Resultssupporting

confidence: 57%

PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions

2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…46 γ-Secretase is a transmembrane protein complex that mediates the final cleavage of APP which eventually liberates Aβ. 47 γ-Secretase inhibitors were shown to be a potential approach for treating Alzheimer's, 4 but there are worries about their deleterious side effects, namely, worsening of the cognitive, functional, and clinical performances. 48 In ophthalmology, a recent study on rats concluded that γ-Secretase inhibitors might provide a therapeutic approach in prevention and treatment of subretinal fibrosis in neovascular AMD and other fibrovascular diseases.…”

Section: High Yield Medical Reviewsmentioning

confidence: 99%

Ophthalmology Perspective on The Theory of Amyloid Beta Toxicity: Implications on Future Studies

AlRyalat,

Alshrouf,

AlMomani

et al. 2024

HYMR

View full text Add to dashboard Cite

Background: The debate about the theory of amyloid beta (Aβ) toxicity grew after the recent approval of the Alzheimer's drug Aducanumab. This was especially true after one of the first articles to bring up this theory was recently criticized for being questionable. Several studies in the field of ophthalmology also used the same theory of Aβ toxicity. Methods: We searched PubMed for ophthalmology-related articles on until January 2024, mentioning amyloid beta to study the consequences of such data concerns and questioned the pathogenic role for Aβ. We will examine the breadth of Aβ-related ophthalmology articles, with an emphasis on those that address Aβ toxicity theory. Results: There was a total of 451 articles in the field of ophthalmology that talked about Aβ. Before 2007, the number of articles did not exceed 10 per year. Since 2007, the number of articles published each year has gone up. In 2007, 14 articles were published, by 2021, 38 articles were published each year before decreasing to 24 articles by 2023. The 2006 article by Lesne et al. was cited 1216times in PubMed. When both searches were put together, a total of seven ophthalmology-related articles that cited Lesne et al's article were found, which we discussed in this review article. Conclusion: Most articles on ophthalmology saw amyloid beta as a diagnostic biomarker, but only a few findings demonstrated that it could be toxic. Most of the time, Aβ was talked about in relation to the retina and its age-related disease, age-related macular degeneration.

show abstract

Modeling of Dipeptide Sulfonamides as Anti-Plasmodial Drugs: Synthesis, Characterization, DFT and In Silico Studies

Ekoh,

Timothy,

Asogwa

et al. 2024

Chemistry Africa

View full text Add to dashboard Cite

Insight γ-Secretase: Structure, Function, and Role in Alzheimer’s Disease

Cited by 6 publications

References 0 publications

PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions

PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions

Ophthalmology Perspective on The Theory of Amyloid Beta Toxicity: Implications on Future Studies

Modeling of Dipeptide Sulfonamides as Anti-Plasmodial Drugs: Synthesis, Characterization, DFT and In Silico Studies

Contact Info

Product

Resources

About