scholarly journals Neurotoxic astrocytes secreted glypican-4 drives Alzheimer’s tau pathology

2020 ◽  
Author(s):  
Ana Pereira ◽  
Sivaprakasam Ramamoorthy
Keyword(s):  
Late Onset ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tau Pathology ◽  
Unfolded Protein ◽  
Density Lipoprotein Receptor ◽  
Protein Response ◽  
Lipoprotein Receptor Related Protein

Abstract Apolipoprotein E4 (APOE4) is the most crucial genetic risk factor of late-onset Alzheimer’s disease (AD). However, the mechanism through which APOE4 induces AD risk remains unknown. Here, we report the astrocyte-secreted protein glypican-4 (GPC-4), as a novel binding partner of APOE4, drives tau pathology. APOE4-carrying AD patients display more tau accumulation compared to APOE4-noncarring AD patients. GPC-4 is highly expressed in APOE4 AD patients, and is regulated by microglial factors via NF-κB signaling pathway. The astrocyte-secreted GPC-4 induced both tau accumulation and spreading in vitro and in vivo. Further, GPC-4 is required for APOE4-mediated surface trafficking of low-density lipoprotein receptor-related protein 1 (LRP1) and tau propagation. GPC-4 activates unfolded protein response (UPR) pathway IRE1α, and pharmacological inhibition of IRE1α with KIRA6 blocks GPC-4 induced tau propagation. Together, our data comprehensively demonstrate that the APOE4-induced AD risk is directly mediated by GPC-4, and that perturbing GPC-4 induced IRE1α pathway has therapeutic opportunities.

scholarly journals Neurotoxic astrocytic glypican-4 drives APOE4-dependent tau pathology

2021 ◽  
Author(s):  
Sivaprakasam Ramamoorthy ◽  
Kirill Gorbachev ◽  
Ana Pereira
Keyword(s):  
Late Onset ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Brain Regions ◽  
Tau Proteins ◽  
Tau Pathology ◽  
Density Lipoprotein Receptor ◽  
Apoe Receptor ◽  
The Brain

Apolipoprotein E4 (APOE4) is the crucial genetic risk factor of late-onset Alzheimer disease (AD). Aggregation of tau proteins into insoluble filaments and their spreading across the brain regions are major drivers of neurodegeneration in tauopathies, including in AD. However, the exact mechanisms through which APOE4 induces tau pathology remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), a novel binding partner of APOE4, drives tau pathology. GPC-4 preferentially interacts with APOE4 in comparison to other APOE isoforms and post-mortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. The astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9 mediated activation of GPC-4 in a tauopathy animal model robustly induced tau pathology. Further, APOE4-induced tau pathology was greatly diminished in the absence of GPC-4. We found that GPC-4 promoted the stabilization of the APOE receptor low-density lipoprotein receptor-related protein 1 (LRP1) on the cellular surface, which effectively facilitates endocytosis of tau protein. Together, our data comprehensively demonstrate that one of the key APOE4-induced tau pathologies is directly mediated by GPC-4.

scholarly journals The Low-Density Lipoprotein Receptor-Related Protein (LRP) Mediates Clearance of Coagulation Factor Xa In Vivo

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 555-560 ◽  
Author(s):  
Masaaki Narita ◽  
Amy E. Rudolph ◽  
Joseph P. Miletich ◽  
Alan L. Schwartz
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Lipoprotein Receptor ◽  
Factor X ◽  
Receptor Associated Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

Abstract Blood coagulation factor X plays a pivotal role in the clotting cascade. When administered intravenously to mice, the majority of activated factor X (factor Xa) binds to α2-macroglobulin (α2M) and is rapidly cleared from the circulation into liver. We show here that the low-density lipoprotein receptor-related protein (LRP) is responsible for factor Xa catabolism in vivo. Mice overexpressing a 39-kD receptor-associated protein that binds to LRP and inhibits its ligand binding activity displayed dramatically prolonged plasma clearance of 125I-factor Xa. Preadministration of α2M-proteinase complexes (α2M*) also diminished the plasma clearance of125I-factor Xa in a dose-dependent fashion. The clearance of preformed complexes of 125I-factor Xa and α2M was similar to that of 125I-factor Xa alone and was also inhibited by mice overexpressing a 39-kD receptor-associated protein. These results thus suggest that, in vivo, factor Xa is metabolized via LRP after complex formation with α2M.

A Novel Low-Density Lipoprotein Receptor-Related Protein Mediating Cellular Uptake of Apolipoprotein E-Enriched β-VLDL in Vitro†,‡

Biochemistry ◽  
2000 ◽  
Vol 39 (51) ◽  
pp. 15817-15825 ◽  
Author(s):  
Takuya Sugiyama ◽  
Hidetoshi Kumagai ◽  
Yoshihiro Morikawa ◽  
Yoichiro Wada ◽  
Akira Sugiyama ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Cellular Uptake ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Related Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

scholarly journals A novel peroxisome proliferator response element modulates hepatic low-density lipoprotein receptor gene transcription in response to PPARδ activation

2015 ◽  
Vol 472 (3) ◽  
pp. 275-286 ◽  
Author(s):  
Vikram R. Shende ◽  
Amar Bahadur Singh ◽  
Jingwen Liu
Keyword(s):  
Gene Transcription ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Density Lipoprotein Receptor ◽  
Peroxisome Proliferator Response Element

PPARδ activation beneficially regulates lipid metabolism. We have now identified a novel function of PPARδ that increases LDL receptor gene transcription in hepatic cells in vitro and in vivo through direct binding to a PPRE motif on LDLR promoter.

scholarly journals Low-Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity

2018 ◽  
Author(s):  
Wei-Chun Chang ◽  
Hsiao-Ching Wang ◽  
Wei-Chung Cheng ◽  
Juan-Cheng Yang ◽  
Wei-Min Chung ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Bioinformatics Analyses ◽  
Density Lipoprotein Receptor ◽  
Cisplatin Sensitivity

Platinum-based therapy remains the cornerstone for cancer patient management; however, its efficacy varies. This study demonstrated the differential expressions of low-density lipoprotein receptor (LDLR) in subtypes of epithelial ovarian carcinoma (EOC) determines cisplatin sensitivity. It's sensitive in serous EOCs (low LDLR), where insensitive in endometrioid and clear cell EOCs (high LDLR). Meanwhile, knocked-down or overexpressed LDLR in EOC could reversed the chemosensitivity pattern both in vitro and in vivo. Mechanistic dissection with transcriptome vs. lipidome trans-omics analyses elucidated the LDLR-->LPC (Lyso-PhosphotidylCholine)-->FAM83B (phospholipase-related)-->FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis in cisplatin insensitivity. Implementing LPC-liposome encapsulated cisplatin could facilitate DNA-adduct formation via lipid droplets (LDs) delivery. Furthermore, Bioinformatics analyses found that the LDL/R-->LD homeostasis alteration is critical for therapeutic prognosis. Lastly, using LPC-liposome-cisplatin improved cisplatin sensitivities in gastric cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma cells. In conclusion, this report discovered a LDL/R-reprogrammed transcriptome-lipidome network, by which impulses platinum insensitivity and disease outcome. The drug specific lipidome for liposome manufacture might be an efficienct pharmaceutics strategy for chemoagents.

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