Low-density Lipoprotein Receptor-related Protein Research Articles

Signatures of natural selection may indicate a genetic basis for the beneficial effects of oily fish intake in indigenous people from coastal Ecuador.

Atahualpa is a rural village located in coastal Ecuador, a region that has been inhabited by people as early as 10,000 years ago. The traditional diet of their indigenous inhabitants is rich in oily fish and they have, therefore, served as a model for investigating the beneficial effects of such a diet. However, the genetic background of this population has not been studied. In this study, we sequenced the genomes of Atahualpa residents to look for variants under natural selection, which could mediate the effects of oily fish intake. DNA was extracted from 50 blood samples from randomly selected individuals recruited in the Atahualpa Project Cohort. After applying various filters, we calculated genome-wide genotype likelihoods from 33 samples, and combined data from those samples with data from other populations to investigate how the Atahualpa population is genetically related to these populations. Using selection scans, we identified signals of natural selection that may explain the above-mentioned dietary effects. The genetic ancestry in Atahualpa residents is 94.1% of indigenous American origin, but is substantially diverged from other indigenous populations in neighboring countries. Significant signatures of natural selection were found in the Atahualpa population, including a broad selection signal around the SUFU gene, which is a repressor of Hedgehog pathway signaling and associated with lipid metabolism, and another signal in the upstream region of LRP1B which encodes low-density lipoprotein (LDL) receptor related protein 1B. Our selection study reveals genes under selection in the Atahualpa population, which could mediate the beneficial effects of oily fish intake in this population.

Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. Lrp1 deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification. These abnormalities, which resemble phenotypes associated with Wnt signalling pathways, result in severe and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical Wnt/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic degradation and recycling. In the developing limbs, LRP1 partially colocalises with Wnt5a and its deficiency alters abundance and distribution of Wnt5a and Vangl2. Finally, using Xenopus as a model system, we show the regulatory role for LRP1 in Wnt/PCP signalling. We propose that in skeletal progenitors, LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating Wnt signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.

Extracellular calreticulin regulates fibrogenic and immunogenic properties of hepatic stellate cells.

Liver fibrosis is a persistent damage repair response triggered by various etiological factors, resulting in an excessive accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HpSCs) are the primary source of ECM proteins. Therefore, specifically targeting HpSCs has become a crucial approach for treating liver fibrosis. Calreticulin (CRT) is a molecular chaperone mainly located in the endoplasmic reticulum (ER), regulating protein folding and calcium homeostasis. Recently, CRT has gained much attention for its role outside the ER, particularly at the cell surface and extracellular space, acting as an immunomodulatory protein. The current study investigates the role of extracellular CRT in hepatic injury and its effects on HpSCs. Elevated levels of circulating CRT were observed in mouse models of liver injury, suggesting that hepatic injury may trigger CRT release. Extracellular CRT was found to moderately inhibit HpSC viability and induce morphological changes. Additionally, CRT treatment led to a decrease in α-smooth muscle actin and an upregulation of matrix metalloproteinase-2 and -9, indicating a potential fibrolytic effect. Immunomodulatory activities of CRT were also noted, as it increased cytokine expression in both macrophages and HpSCs. These effects were partially mediated through low-density lipoprotein receptor-related protein 1 (LRP1), as evidenced by altered cytokine expression upon co-treatment with a known LRP1 ligand receptor-associated protein (RAP). Overall, this study elucidates the complex role of extracellular CRT in liver injury and its potential impact on HpSC behavior and immune responses.

LRP4 and Agrin Are Modulated by Cartilage Degeneration and Involved in β-Catenin Signaling in Human Articular Chondrocytes

We investigated the roles of low-density lipoprotein receptor-related protein (LRP) 4 and its ligand Agrin in the pathophysiology of cartilage degeneration. Immunohistochemical analysis of human normal articular cartilage and cartilage tissues from patients with osteoarthritis (OA) obtained during surgery of the knee joint showed marked LRP4 expression in the early stages of OA, which then decreased with cartilage degeneration, whereas Agrin was consistently increased with cartilage degeneration. In normal human articular chondrocytes (NHACs), mild cyclic tensile strain (CTS) (0.5 Hz, 5% elongation, 2 h) increased the expression of LRP4 and aggrecan (ACAN), while intense CTS (0.5 Hz, 10% elongation, 6 h) increased the expression of Agrin without affecting LRP4 expression. Treatment with recombinant human (rh) Agrin downregulated the mRNA expression of LRP4 and ACAN, but upregulated the expression of LRP5/6, SRY-box transcription factor 9 (SOX9), Runt-related transcription factor 2 (RUNX2), and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4). Immunocytochemistry and Western blot analysis showed that rhAgrin treatment upregulated the expression of β-catenin and SOX9. Agrin knockdown by siAGRN transfection partially reduced the nuclear protein expression of β-catenin, which was increased with intense CTS. LRP4 knockdown by siLRP4 transfection increased the expression of LRP5/6, SOX9, RUNX2, ADAMTS-4, and Agrin. These results suggested that intense CTS increases the expression of Agrin, which might interfere with the role of LRP4 in the inhibition of LRP5/6 and their downstream β-catenin signaling, leading to cartilage degeneration.

Effect of PCSK9 Inhibitors on Regulators of Lipoprotein Homeostasis, Inflammation and Coagulation

Background: PCSK9 inhibitors (PCSK9i) represent a newer form of atherosclerosis treatment. Inflammation and haemostasis are key processes in the development of atherosclerosis. In this study, we investigated the influence of therapy with PCSK9i in patients with coronary artery disease (CAD) on regulators for lipoprotein homeostasis, inflammation and coagulation. Methods: Using quantitative polymerase chain reaction (qPCR), we measured the expression of the genes involved in lipoprotein homeostasis, namely for sterol regulatory element-binding protein 1 (SREBP1), SREBP2, low-density lipoprotein receptor (LDLR), hepatic lipase type C (LIPC), LDLR-related protein 8 (LRP8), and the genes associated with inflammation and coagulation, such as cluster of differentiation (CD) 36 (CD36), CD63, and CD14 in 96 patients with CAD and 25 healthy subjects. Results: Significant differences in the expression of the investigated genes between patients and healthy controls were found. Treatment with PCSK9i also resulted in significant changes in the expression of all studied genes. Conclusions: We established that PCSK9i may have a significant effect on the gene expression of lipid regulators, inflammatory markers, and coagulation parameters, independent of their lipolytic effect.

LRP5 Down-Regulation Exacerbates Inflammation and Alveolar Bone Loss in Periodontitis by Inhibiting PI3K/c-FOS Signalling.

To investigate the involvement of low-density lipoprotein receptor-related protein 5 (LRP5) in inflammation and alveolar bone loss in periodontitis. Gingival tissues were obtained from 10 periodontitis patients and 10 healthy individuals. Wild-type (WT) and osteoblast-specific Lrp5 conditional knock-out C57BL/6 (LRP5fl/fl;Oc-Cre) mice were used to establish a ligature-induced mouse model of periodontitis. Human periodontal ligament stem cells (hPDLSCs) were isolated and used to further verify the mechanism through which LRP5 mediates periodontitis invitro. Micro-computed tomography, haematoxylin and eosin staining, immunohistochemistry, quantitative reverse-transcription PCR, western blotting, enzyme-linked immunosorbent assay and RNA sequencing were performed to explore the role of LRP5 in periodontitis and the underlying mechanism. LRP5 expression was down-regulated in human/mouse periodontal tissues compared to that in healthy controls. Compared to those in wild-type mice, the periodontal tissues of LRP5fl/fl;Oc-Cre mice had increased alveolar bone loss, higher proinflammatory cytokine levels, and lower osteogenesis-related factor expression. LRP5 expression was down-regulated in hPDLSCs after lipopolysaccharide treatment invitro. LRP5 knockdown increased proinflammatory cytokine production and inhibited osteoblastogenesis by inhibiting PI3K/c-FOS signalling. LRP5 down-regulation exacerbates inflammation and alveolar bone loss in periodontitis by inhibiting PI3K/c-FOS signalling, suggesting LRP5 as a potential therapeutic target for periodontitis.

Cellular expression of low-density lipoprotein receptor-related protein 1 and amyloid beta deposition in human and rat epileptogenic brain.

Decreased capillary expression of low-density lipoprotein receptor-related protein 1 (LRP1) has been linked to increased brain amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Aβ accumulation has also been observed in (a subset of) temporal lobe epilepsy (TLE) patients, suggesting a potential link between epilepsy and AD. This study examines cellular LRP1 expression in human and rat epileptogenic brain tissue to explore LRP1's role in epilepsy. LRP1 expression and localization were analyzed in hippocampal sections from patients with status epilepticus (SE, n=12), TLE (n=12), autopsy controls (n=20), and AD (n=10) using immunohistochemistry. Soluble Aβ levels and deposits were compared across TLE, AD, and control tissues. LRP1 expression was also studied in an electrical post-SE rat model of TLE. Decreased capillary LRP1 expression was found in both human and rat brain tissue (SE and TLE). Higher LRP1 expression was detected in CA1 neurons (only in human TLE) and glial cells (SE and TLE). Aβ deposits were observed in only one out of 12 TLE patients, and soluble Aβ levels were not significantly elevated. In contrast, AD patients showed decreased capillary LRP1 expression accompanied by Aβ plaques and increased soluble Aβ40/42 levels. The significant reduction in LRP1 expression in brain capillaries in both adult human and rat TLE was not clearly associated with notable Aβ accumulation implying that alternative amyloid clearance mechanisms beyond LRP1 in blood vessels might be at play. It also supports previous findings indicating that Aβ pathology may be less prominent in adult TLE than some studies suggest.

Palm Tocotrienol Activates the Wnt3a/β-Catenin Signaling Pathway, Protecting MC3T3-E1 Osteoblasts from Cellular Damage Caused by Dexamethasone and Promoting Bone Formation.

Background and aim: Prolonged glucocorticoid (GC) treatment increases oxidative stress, triggers apoptosis of osteoblasts, and contributes to osteoporosis. Tocotrienol, as an antioxidant, could protect the osteoblasts and preserve bone quality under glucocorticoid treatment. From this study, we aimed to determine the effects of tocotrienol on MC3T3-E1 murine pre-osteoblastic cells treated with GC. Methods: MC3T3-E1 cells were exposed to dexamethasone (150 µM), with or without palm tocotrienol (PTT; 0.25, 0.5, and 1 µg/mL). Cell viability was measured by the MTS assay. Alizarin Red staining was performed to detect calcium deposits. Cellular alkaline phosphatase activity was measured to evaluate osteogenic activity. The expression of osteoblastic differentiation markers was measured by an enzyme-linked immunoassay. Results: Enhanced matrix mineralization was observed in the cells treated with 0.5 µg/mL PTT, especially on day 18 (p < 0.05). The expression of Wnt3a, β-catenin, collagen 1α1, alkaline phosphatase, osteocalcin, low-density lipoprotein receptor-related protein 6, and runt-related transcription factor-2 were significantly increased in the PTT-treated groups compared to the vehicle control group, especially at 0.5 µg/mL of PTT (p < 0.05) and on day 6 of treatment. Conclusions: PTT maintains the osteogenic activity of the dexamethasone-treated osteoblasts by promoting their differentiation.

Peptide-drug conjugates repolarize glioblastoma-associated macrophages to resensitize chemo-immunotherapy of glioblastoma.

The prevalent tumor-supporting glioblastoma-associated macrophages (GAMs) promote glioblastoma multiforme (GBM) progression and resistance to multiple therapies. Repolarizing GAMs from tumor-supporting to tumor-inhibiting phenotype may troubleshoot. However, sufficient accumulation of drugs at the GBM site is restricted by blood-brain barrier (BBB). Herein, we designed peptide-drug conjugates (PDCs) by conjugating camptothecin or resiquimod to a tandem peptide composed of matrix metalloproteinase 2-responsive peptide and angiopep-2 via disulfonyl-ethyl carbonate/carbamate (MAPDCs). The mixed self-assembly MAPDCs could recognize low-density lipoprotein receptor-related protein 1 (LRP1) to facilitate BBB transport. Once reaching the GBM site, the responsive peptide would be cleaved to shed the angiopep-2, blocking abluminal LRP1-mediated brain-to-blood efflux and enhancing drug retention. Sequentially, drugs are released under the high level of intracellular glutathione. In vivo studies demonstrated that MAPDCs repolarized GAMs, boosted immune response, and resensitized chemotherapeutic toxicity, offering a much-improved anti-GBM effect. The effectiveness of MAPDCs validates GAMs as therapeutic target and PDCs as versatile brain delivery system with high design flexibility.

Oleandrin inhibits osteoclast differentiation by targeting the LRP4/MAPK/NF-κB signalling pathway to treat osteoporosis.

Osteoporosis is a common inflammation-related disease in which the release of proinflammatory cytokines promotes bone loss. Oleandrin is a monomer compound extracted from the leaves of the Nerium oleander plant, has been shown to exert an anti-inflammatory effect on a variety of inflammation-related diseases. However, its role in osteoporosis and the underlying mechanisms remain unclear. In this study, Oleandrin was shown to reduce bone loss in ovariectomy-induced osteoporotic mice in vivo. Additionally, Oleandrin inhibited RANKL-induced osteoclast differentiation in a concentration-dependent manner in vitro. Signalling pathway studies showed that Oleandrin could inhibit osteoclast differentiation by targeting MAPK and NF-κB signalling pathways. Further mechanistic studies showed that Oleandrin binds to low-density lipoprotein receptor-related protein 4 in osteoclast, thereby exerting inhibitory effects on osteoclast differentiation. In conclusion, this study lays the foundation for further research on the anti-inflammatory and anti-osteoporotic effects of Oleandrin on osteoporosis and its underlying mechanism and provides new possibilities for the treatment of osteoporosis.

Low-density lipoprotein receptor-related protein 6 ameliorates cardiac hypertrophy by regulating CTSD/HSP90α signaling during pressure overload.

Pressure overload induces pathological cardiac remodeling, including cardiac hypertrophy and fibrosis, resulting in cardiac dysfunction or heart failure. Recently, we observed that the low-density lipoprotein receptor-related protein 6 (LRP6), has shown potential in enhancing cardiac function by mitigating cardiac fibrosis in a mouse model subjected to pressure overload. In this study, we investigated the role of LRP6 as a potential modulator of pressure overload-induced cardiac hypertrophy and elucidated the underlying molecular mechanisms. We performed transverse aortic constriction (TAC) to induce pressure overload in cardiomyocyte-specific LRP6 overexpression mice (LRP6-overmice) and in control mice (α-myosin heavy chain (α-MHC) Mer-Cre-Mer Tg mice or namedMCM mice). Cardiac function and hypertrophy were assessed using echocardiography. LRP6-over mice showed improved cardiac function and reduced hypertrophy after TAC, compared with MCM mice. We also applied mechanical stretch to cultured neonatal rat cardiomyocytes to model pressure overload in vitro. Mass spectrometry analysis showed that LRP6 interacts with HSP90α and cathepsin D (CTSD) in cardiomyocytes under mechanical stress. Further analysis demonstrated that LRP6 facilitates CTSD-mediated degradation of HSP90α, consequently inhibiting β-cateninactivation and reducing cardiac hypertrophy post-TAC. Treatment with recombinantHSP90α protein or the CTSD inhibitor, pepstatin A, partly abolished the protective effect of LRP6 overexpression on myocardial hypertrophy and cardiac function after TAC in mice. Collectively, our data suggest that LRP6 protects against pressure overload-induced myocardial remodeling and that the CTSD/HSP90α/β-catenin axis may be a potential therapeutic target.

PCSK9 V474I germline variant drives breast cancer metastasis.

Abstract Breast cancer metastasis remains the leading cause of mortality in patients, yet its mechanisms are poorly understood. A recent Cell paper highlights the pivotal role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) V474I germline variant in driving metastatic progression through suppression of the low-density lipoprotein receptor related protein 1 (LRP1) receptor, revealing novel therapeutic opportunities and genetic insights.

The LDL Receptor-Related Protein 1: Mechanisms and roles in promoting Aβ efflux transporter in Alzheimer's disease.

The LDL Receptor-Related Protein 1(LRP1), a member of the Low-density Lipoprotein (LDL) receptor family, is a multifunctional cellular transporter and signaling receptor, this includes regulation of lipid metabolism, cell migration and signaling. Abnormal accumulation of amyloid beta (Aβ) in the brain is thought to be the main pathological change in Alzheimer's disease. By binding to a variety of ligands, LRP1 is involved in the internalization and degradation of Aβ, thereby affecting the course of Alzheimer's disease (AD). Here, we discuss the main mechanisms by which LRP1 mediates Aβ degradation and clearance and several current therapeutic approaches targeting LRP1. Finally, we concluded that modulating the expression level of LRP1 is an effective way to attenuate Aβ deposition and ameliorate AD. Abbreviations: LRP1, LDL Receptor-Related Protein 1;LDL, Low Density Lipoprotein; Aβ, amyloid beta; AD, Alzheimer's disease; APP, amyloid precursor protein; ApoE, apolipoprotein E; TGF, growth factor; MMP, matrix metalloproteinase;TAT, thrombin-antithrombin complex; BBB, blood-brain barrier; MMP-9,cyclophilin A (CypA)-matrix metalloproteinase-9; VMC, Vascular Mural Cell; IDE,insulin degrading enzyme; EVs, extracellular vesicles; sLRP1,shed LRP1; BDNF, brain-derived neurotrophin; IGF-1,insulin-like growth factor 1; NGF, nerve growth factor; MAPK,mitogen-activated protein kinase; ERK1/2,exogenous signal-regulated kinase1/2;JNK, c-Jun amino-terminal kinase; TLR4, toll-like receptor 4; NF-κB,nuclear factor-κB; GCAP,guanylate cyclase-activating protein; KD, ketogenic diet;KB, ketone body; BLECs,Brain-like endothelial cell; BYHWD, Buyang Huanwu decoction; LGZG, Linguizhugan decoction;P- gp, P-glycoprotein;PPARγ, Peroxisome proliferator-activated receptor γ;SP16,SERPIN peptide 16; Asx, Astaxanthin; Bex, Bexarotene.

High-throughput microfluidic spheroid technology for early detection of colistin-induced nephrotoxicity with gradient-based analysis.

Colistin is essential for treating multidrug-resistant Gram-negative bacterial infections but has significant nephrotoxic side effects. Traditional approaches for studying colistin's nephrotoxicity are challenged by the rapid metabolism of its prodrug, colistin methanesulfonate and the difficulty of obtaining adequate plasma from critically ill patients. To address these challenges, we developed the Spheroid Nephrotoxicity Assessing Platform (SNAP), a microfluidic device that efficiently detects colistin-induced toxicity in renal proximal tubular epithelial cell (RPTEC) spheroids within 48 hours using just 200 μL of patient plasma. Our findings demonstrate that SNAP not only promotes higher expression of kidney-specific markers aquaporin-1 (AQP1) and low-density lipoprotein receptor-related protein 2 (LRP2) compared to traditional two-dimensional (2D) cultures, but also exhibits increased sensitivity to colistin, with significant toxicity detected at concentrations of 50 μg ml-1 and above. Notably, SNAP's non-invasive method did not identify nephrotoxicity in plasma from healthy donors, thereby confirming its physiological relevance and showcasing superior sensitivity over 2D cultures, which yielded false-positive results. In clinical validation, SNAP accurately identified patients at risk of colistin-induced nephrotoxicity with 100% accuracy for both early and late onset and demonstrated a 75% accuracy rate in predicting the non-occurrence of nephrotoxicity. These results underline the potential of SNAP in personalized medicine, offering a non-invasive, precise and efficient tool for the assessment of antibiotic-induced nephrotoxicity, thus enhancing the safety and efficacy of treatments against resistant bacterial infections.

Evaluation of LRP6, SFRP3, and DVL1 Protein Concentrations in Serum of Patients with Gastroenteropancreatic or Bronchopulmonary Neuroendocrine Tumors.

Introduction: Neuroendocrine tumors are a diverse group of tumors predominantly found in the gastrointestinal tract or respiratory system. Methods: This retrospective study aimed to measure the serum concentrations of LRP6 (low-density lipoprotein receptor-related protein 6), SFRP3 (secreted frizzled-related protein 3), and DVL1 (segment polarity protein dishevelled homolog) using the ELISA method in patients with NETs (N = 80) and a control group (N = 62). We evaluated the results against various demographic, clinicopathological, and biochemical characteristics. Results: Our analyses revealed that the concentration of SFRP3 in patients with neuroendocrine tumors was significantly elevated (p < 0.001) compared to the control group. Additionally, DVL1 concentrations were significantly higher (p < 0.01) in patients with BP-NETs compared to GEP-NETs. Furthermore, DVL1 analysis showed a moderate negative correlation with chromogranin A (p < 0.001) and weak negative correlations with serotonin (p < 0.05) and 5-HIAA (p < 0.05). Significant negative correlations were also observed between DVL1 and age in the control group (p < 0.01), and between LRP6 and Ki-67 in the study group. Conclusions: These results suggest that changes in the SFRP3 and DVL1 pathways play a key role in NET development. Elevated levels of these proteins highlight their importance in tumor biology, with SFRP3 and DVL1 potentially being crucial in NET molecular mechanisms. Further research is needed to explore their roles and potential in diagnosis and treatment.

LRP4 mutations promote tumour progression and resistance to anti-PD-1 therapy in recurrent hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) recurrence is a major factor limiting long-time survival and the cause of most deaths in patients with HCC. However, molecular characterisation and potential therapeutic targets of recurrent HCC remain mostly unknown. We performed whole-exome sequencing (WES) in 63 matched primary and recurrent HCC tumours and combined the data with whole-genome sequencing (WGS) results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 (LRP4) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumours and only 0.97% (3/309) of primary tumours (P<0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumour progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoural conventional type 1 dendritic cell and CD8+ T cell infiltration by repressing CCL4 expression and secretion through activation of β-catenin signalling, resulting in resistance to anti-programmed cell death protein-1 (PD-1) therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-PD-1 treatment after their second resection surgery. A β-catenin inhibitor reversed LRP4-induced resistance to anti-PD-1 therapy in humanised tumour-bearing mice. Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-PD-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.

Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms.

Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown. We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1). Dynamin inhibition decreased microglial endocytosis of all tested tau species. Meanwhile, HSPG antagonism blocked only fibril uptake, and LRP1 antagonism or genetic depletion inconsistently inhibited the endocytosis of fibrils and monomers. Cre recombinase robustly enhanced tau uptake with partial selectivity for fibrils. These data show that microglia take up both tau monomers and aggregates via a dynamin-dependent form of endocytosis (eg, CME) but may differ in using HSPGs for entry depending on species. Microglial endocytosis of tau monomers and fibrils is dynamin-dependent. HSPG antagonism blocks microglial uptake of tau fibrils but not monomers. LRP1 antagonism or knockdown inconsistently inhibits tau uptake. TAT-Cre stimulates semi-selective uptake of fibrils over monomers.

Possible Involvement of Hippocampal miR-539-3p/Lrp6/Igf1r Axis for Diminished Working Memory in Mice Fed a Low-Carbohydrate and High-Protein Diet.

A low-carbohydrate and high-protein (LC-HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function with the decreased expression of hippocampal insulin-like growth factor-1 receptor (IGF-1R) among healthy mice. However, the precise mechanisms underlying this phenomenon remain unexplored. Eight-week-old male C57BL/6 mice were divided into the LC-HP diet-fed group (25.1% carbohydrate, 57.2% protein, and 17.7% fat as percentages of calories; n=10) and the control diet-fed group (58.9% carbohydrate, 24.0% protein, and 17.1% fat; n=10). After 4 weeks, all mice underwent the Y-maze test, followed by analyses of hippocampal mRNA and miRNA expressions. We revealed that feeding the LC-HP diet suppressed working memory function and hippocampal Igf1r mRNA levels in mice. Sequencing of hippocampal miRNA demonstrated 17 upregulated and 27 downregulated miRNAs in the LC-HP diet-fed mice. Notably, we found decreased hippocampal mRNA levels of low-density lipoprotein receptor-related protein 6 (Lrp6), a gene modulated by miR-539-3p, in mice fed the LC-HP diet. Furthermore, a significant positive correlation was observed between Lrp6 and Igf1r mRNA levels in the hippocampus. These findings suggest that LC-HP diets may suppress hippocampal function via the miR-539-3p/Lrp6/Igf1r axis.

Temperature induces brain-intake shift of recombinant high-density lipoprotein after traumatic brain injury

Traumatic brain injury (TBI) is one of the leading public health concerns in the world. Therapeutic hypothermia is routinely used in severe TBI, and pathophysiological hyperthermia, frequently observed in TBI patients, has an unclear impact on drug transport in the injured brain due to a lack of study on its effects. We investigated the effect of post-traumatic therapeutic hypothermia at 33°C and pathophysiological hyperthermia at 39°C on brain transport and cell uptake of neuroprotectants after TBI. Recombinant high-density lipoprotein (rHDL), which possesses anti-inflammatory, antioxidant activity, and blood–brain barrier (BBB) permeability, was chosen as the model drug. First, we found that mild hypothermia and hyperthermia impaired rHDL transport to the brain and lesion targeting in controlled cortical impact mice. Second, we investigated the temperature-induced rHDL uptake shift by various brain cell types. Mild hypothermia impeded the uptake of rHDL by endothelial cells, neurons, microglia, and astrocytes. Hyperthermia impeded the uptake of rHDL by endothelial cells and neurons while promoting its uptake by microglia and astrocytes. In an attempt to understand the mechanisms behind the above phenomena, it was found that temperature induced brain-intake shift of rHDL through the regulation of low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) stability in brain cells. We therefore reported the full view of the temperature-induced brain-intake shift of rHDL after TBI for the first time. It would be of help in coordinating pharmacotherapy with temperature management in individualization and precision medicine.Graphical

LRP1B mutation is associated with lymph node metastasis in endometrial carcinoma: A clinical next-generation sequencing study.

This study aims to investigate the mutation status and protein expression of low-density lipoprotein receptor-related protein 1B (LRP1B) in endometrial cancer, and analyze its association with lymph node metastasis (LNM) in endometrial cancer. Targeted next-generation sequencing (NGS) was conducted on both tumor tissues and paired blood DNA obtained from 94 endometrial cancer patients, followed by comprehensive analysis. Additionally, immunohistochemistry (IHC) was used to explore the correlation between LRP1B protein expression levels, its gene mutation status, and LNM. LRP1B mutation was observed in 19 patients (20.2%). Our results revealed that LRP1B mutation frequencies were significantly different between endometrial cancer with or without LNM (P = 0.038). Multivariate analysis indicated that LRP1B mutation was a favorable predictor (odds ratio 0.09; 95% confidence interval 0.01-0.95; P = 0.045) for LNM in endometrial cancer. Further analysis revealed that combination of LRP1B mutation with clinical variants (LVSI and histological subtype) yielded a higher area under the curve value of 0.871) and patients harboring LRP1B mutated-type were less likely to develop LNM. On integrated analysis, the concordance between LRP1B NGS and LRP1B IHC was 73.3%. This study utilizes targeted NGS to uncover the relationship between LRP1B mutation and LNM status, contributing to the development of primary prevention and proactive treatment strategies.