Blood–Brain Barrier Breakdown in Alzheimer’s Disease: Mechanisms and Targeted Strategies

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(22), P. 16288 - 16288

Published: Nov. 14, 2023

The blood-brain barrier (BBB) is a unique and selective feature of the central nervous system's vasculature. BBB dysfunction has been observed as an early sign Alzheimer's Disease (AD) before onset dementia or neurodegeneration. intricate relationship between pathogenesis AD, especially in context neurovascular coupling overlap pathophysiology neurodegenerative cerebrovascular diseases, underscores urgency to understand BBB's role more deeply. Preserving restoring function emerges potentially promising strategy for mitigating progression severity AD. Molecular genetic changes, such isoform ε4 apolipoprotein E (ApoEε4), significant risk factor promoter dysfunction, have shown mediate disruption. Additionally, receptors transporters like low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), receptor advanced glycation end products (RAGEs) implicated AD's pathogenesis. In this comprehensive review, we endeavor shed light on pathogenic therapeutic connections AD BBB. We also delve into latest developments pioneering strategies targeting interventions, addressing its potential carrier. By providing integrative perspective, anticipate paving way future research treatments focused exploiting therapy.

Language: Английский

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Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 8, 2024

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and revolutionary therapeutic target for hypercholesterolemia its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles wide-ranging implications of PCSK9, extending beyond CVD to emphasize significance diverse physiological pathological states, including liver diseases, infectious autoimmune disorders, notably, cancer. Our exploration offers insights into interaction between PCSK9 low-density lipoprotein receptors (LDLRs), elucidating substantial impact on cholesterol homeostasis health. It also details evolution PCSK9-targeted therapies, translating foundational bench discoveries bedside applications optimized patient care. The advent clinical approval innovative inhibitory therapies (PCSK9-iTs), three monoclonal antibodies (Evolocumab, Alirocumab, Tafolecimab) one small interfering RNA (siRNA, Inclisiran), have marked significant breakthrough medicine. These demonstrated unparalleled efficacy mitigating hypercholesterolemia, reducing risks, showcased profound value applications, offering novel avenues promising future personalized medicine disorders. Furthermore, emerging research, inclusive our findings, unveils PCSK9's potential role indicator cancer prognosis prospective application transformative treatment. highlights aberrant expression various forms, association with prognosis, crucial carcinogenesis immunity. In conclusion, this synthesized integrates existing knowledge providing holistic perspective reshaping paradigms across emphasizes effect PCSK9-iT, underscoring advancing landscape biomedical research capabilities heralding new eras

Language: Английский

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The relationship between statin therapy and adipocytokine/inflammatory mediators in dyslipidemic nondiabetic patients: A comparative study

Pharmacia, Journal Year: 2023, Volume and Issue: 70(3), P. 581 - 585

Published: Aug. 7, 2023

Background : Statins have emerged as a vital therapeutic option for dyslipidemia, effectively reducing morbidity and mortality in individuals with various medical conditions. Recent research has shed light on the intricate pathophysiology of atherosclerosis, which involves lipid accumulation inflammatory mediators. This was conducted to assess correlation between statin therapy adipocytokine mediator levels dyslipidemic nondiabetic patients. Methods A total 67 patients were enrolled, alongside 33 healthy controls. The participants categorized into three groups: Group (A), comprising undergoing (n = 34), (B), consisting not receiving 33); (C), controls 33). Results Patients exhibited significant profiles compared Levels cholesterol (TC), triglycerides (TG), very low-density lipoprotein (VLDL), (LDL) higher therapy. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) group than non-statin Additionally, PCSK9 treated rosuvastatin those atorvastatin. Conversely, retinol-binding protein 4 (RBP4) lower Although no difference RBP4 atorvastatin users found, displayed values. study also revealed C-reactive (CRP) group, primarily subgroup, group. Conclusion Statin increased levels, more pronounced rise observed proved protective by CRP

Language: Английский

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Drug development advances in human genetics‐based targets

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

Drug development is a long and costly process, with high degree of uncertainty from the identification drug target to its market launch. Targeted drugs supported by human genetic evidence are expected enter phase II/III clinical trials or be approved for marketing more quickly, speeding up process. Currently, data technologies such as genome-wide association studies (GWAS), whole-exome sequencing (WES), whole-genome (WGS) have identified validated many potential molecular targets associated diseases. This review describes structure, biology, genetics-based beneficial loss-of-function (LOF) mutation (target mutations that reduce disease incidence) over past decade. The feasibility eight LOF (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, INHBE) discovery mainly emphasized, their research prospects challenges discussed. In conclusion, we expect this will inspire researchers use genetics genomics support novel therapeutic direction development, which contribute new repurposing.

Language: Английский

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Hypercholesterolemia and the Increased Risk of Vascular Dementia: a Cholesterol Perspective

Current Atherosclerosis Reports, Journal Year: 2024, Volume and Issue: 26(8), P. 435 - 449

Published: May 30, 2024

Language: Английский

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PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 119, P. 494 - 506

Published: April 22, 2024

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on brain remains largely unexplored. This study aimed assess effects alirocumab, monoclonal antibody targeting PCSK9 lower systemic low-density lipoprotein cholesterol (LDL-C), central nervous system (CNS) pathology rat model chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks 32 male rats subjected 35 % ethanol liquid diet control (n = 8 per group). The evaluated expression, LDL receptor (LDLR) neuroinflammatory markers tissues. Chronic exposure increased expression brain, while alirocumab treatment significantly upregulated LDLR reduced stress neurons vasculature (3-NT, p22phox). also mitigated ethanol-induced microglia recruitment cortex hippocampus (Iba1). Additionally, decreased pro-inflammatory cytokines chemokines (TNF, CCL2, CXCL3) whole tissue attenuated upregulation adhesion molecules (ICAM1, VCAM1, eSelectin). presents novel evidence that diminishes modifies neuroimmune interactions elicited by Further investigation needed elucidate mechanisms which signaling influences context

Language: Английский

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Effects of sodium arsenite exposure on behavior, ultrastructure and gene expression of brain in adult zebrafish (Danio rerio)

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 273, P. 116107 - 116107

Published: Feb. 20, 2024

Arsenic, a common metal-like substance, has been demonstrated to pose potential health hazards and induce behavioral changes in humans rodents. However, the chronic neurotoxic effects of arsenic on aquatic animals are still not fully understood. This study aimed investigate exposure adult zebrafish by subjecting 3-month-old three different sodium arsenite water concentrations: 0 μg/L (control group), 50 μg/L, 500 over period 30 days. To assess risk associated with environment, behavior analysis, transmission electron microscopy techniques, quantitative real-time PCR were employed. The was evaluated using six distinct tests: mirror biting test, shoaling novel tank social preference recognition T maze. Following tests, brains dissected collected for ultrastructural examination gene expression analysis. results revealed that led significant reduction aggression, cohesion, ability, cognition learning, memory capacity zebrafish. Furthermore, ultrastructure genes regulating brain adversely affected exposure.

Language: Английский

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The potential role of PCSK9 inhibitors in heart transplant patients: a case series

Journal of Cardiology & Current Research, Journal Year: 2025, Volume and Issue: 18(1), P. 6 - 10

Published: Jan. 1, 2025

The Proprotein convertase subtilisin/ kexin type 9 inhibitors (PCSK9i) are a novel class of lipid-lowering agents that effectively reduce low-density lipoprotein (LDL) cholesterol levels. use these has expanded to involve recipients solid organ transplants. Method: This case series reports the safety using PCSK9i in three patients who received heart transplants, followed up for lipid profile, and observed incidence coronary artery vasculopathy (CAV) over two years post-treatment. Results: Evolocumab significantly reduced LDL level without drug interaction with immune suppression medication. follow-up evaluation angiogram or myocardial perfusion images confirms freedom from CAV progression. Conclusion: improved profile any adverse effect related combined suppressive therapy. A lack progression was through diagnostic imaging modalities, suggesting potential preventive evolocumab on CAV. However, large-scale, randomized, controlled trials needed confirm efficacy lowering levels, preventing CAV, reducing risk graft rejection transplant (HT) recipients.

Language: Английский

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Assessing the Impact of PCSK9 and HMGCR Inhibition on Liver Function: Drug-Target Mendelian Randomization Analyses in Four Ancestries

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2023, Volume and Issue: 17(1), P. 29 - 40

Published: Sept. 11, 2023

Background & AimsObservational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, disease incidence varies across diverse populations, the long-term hepatic impact of these drugs among non-white Europeans remains largely unknown.MethodsWe use single nucleotide polymorphisms (SNPs) in PCSK9 HMGCR loci from genome-wide association study data low-density lipoprotein cholesterol 4 populations (East Asian [EAS], South [SAS], African [AFR], European [EUR]) to perform drug-target Mendelian randomization investigating relationships between inhibition alanine aminotransferase (ALT), aspartate (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), bilirubin.ResultsAnalyses instruments, including functional variants R46L E670G, failed find evidence for lowering via effects on ALT, AST, GGT, or ALP cohorts. was associated increased direct bilirubin levels EUR (β = 0.089; P value 5.69 × 10–6) and, nominally, AFR 0.181; .044). reduced AST SAS –0.705; .005) EAS –0.096; .03), –2.078; .014), 0.071; .032). Sensitivity analyses using genetic instruments derived circulating protein levels, tissue-specific expression, expression were alignment, strengthening causal inference.ConclusionsWe did not genetically proxied ancestries. We identified possible several ancestries total AST. These findings support safety profiles low hepatotoxic risk populations. Observational unknown. bilirubin. Analyses inference.

Language: Английский

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PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 126, P. 111195 - 111195

Published: Dec. 4, 2023

Ischemic stroke is the second leading cause of death worldwide, and neuroinflammation has been recognized as a critical player in its progression. Meanwhile, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) demonstrated to inhibit inflammatory response. However, effects PCSK9i on ischemic remain unclear require further investigation.

Language: Английский

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