The Intersection of Cerebral Cholesterol Metabolism and Alzheimer's Disease: Mechanisms and Therapeutic Prospects

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e30523 - e30523

Published: April 30, 2024

Alzheimer's disease (AD) is a common neurodegenerative in the elderly, exact pathogenesis of which remains incompletely understood, and effective preventive therapeutic drugs are currently lacking. Cholesterol plays vital role cell membrane formation neurotransmitter synthesis, its abnormal metabolism associated with onset AD. With continuous advancement imaging techniques molecular biology methods, researchers can more accurately explore relationship between cholesterol Elevated levels may lead to vascular dysfunction, thereby affecting neuronal function. Additionally, affect β-amyloid protein, promoting Brain regulated by multiple factors. This review aims deepen understanding subtle homeostasis AD, introduce latest advances cholesterol-regulating AD treatment strategies, inspiring readers contemplate deeply on this complex relationship. Although there still many unresolved important issues regarding risk brain some studies have opposite conclusions, further research needed enrich our understanding. However, these findings expected provide insights for future development strategies targeting homeostasis.

Language: Английский

---

Targeting PCSK9 as a key player in lipid metabolism: exploiting the therapeutic and biosensing potential of aptamers

Lipids in Health and Disease, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 25, 2024

The degradation of low-density lipoprotein receptor (LDLR) is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in elevated plasma concentrations LDL cholesterol. Therefore, inhibiting the interactions between PCSK9 and LDLR a desirable therapeutic goal for managing hypercholesterolemia. Aptamers, which are RNA or single-stranded DNA sequences, can recognize their targets based on secondary structure. Aptamers exhibit high selectivity affinity binding to target molecules. systematic evolution ligands exponential enrichment (SELEX), combination biological approaches, used screen most aptamers vitro. Due unique advantages, have garnered significant interest since discovery found extensive applications various fields. been increasingly utilized development biosensors sensitive detection pathogens, analytes, toxins, drug residues, malignant cells. Furthermore, similar monoclonal antibodies, serve as tools. Unlike certain protein therapeutics, do not elicit antibody responses, modified sugars at 2'-positions generally prevent toll-like receptor-mediated innate immune responses. focus this review aptamer-based targeting application both agents.

Language: Английский

---

The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer’s Disease: A Possible Target for the Disease Treatment

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13637 - 13637

Published: Dec. 20, 2024

Alzheimer’s disease (AD) is a multifactorial neurodegenerative mainly caused by β-amyloid (Aβ) accumulation in the brain. Among several factors that may concur to AD development, elevated cholesterol levels and brain dyshomeostasis have been recognized play relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) protein primarily known regulate plasma low-density lipoproteins (LDLs) rich be one of main causes familial hypercholesterolemia. In addition that, PCSK9 also carry out diverse important activities brain, including control neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, appeared directly involved some principal processes responsible for such as inflammation, oxidative stress, Aβ deposition. On these bases, management might represent promising approach treatment. The purpose this review elucidate role PCSK9, whether or not cholesterol-related, pathogenesis give an updated overview most innovative therapeutic strategies developed so far counteract pleiotropic both humoral focusing particular on their potentiality management.

Language: Английский

---

E3 ubiquitin ligase MARCH1 reduces inflammation and pyroptosis in cerebral ischemia-reperfusion injury via PCSK9 downregulation

Mammalian Genome, Journal Year: 2024, Volume and Issue: 35(3), P. 346 - 361

Published: Aug. 8, 2024

Language: Английский

---

Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence

Drug Development Research, Journal Year: 2023, Volume and Issue: 85(1)

Published: Nov. 9, 2023

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance plasma low‐density lipoprotein cholesterol (LDL‐C). PCSK9 inhibitors are developed to primarily reduce cardiovascular risk by lowering LDL‐C level. Recently, a number pleiotropic extrahepatic functions beyond regulation metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence revealed that may play significant role neurocognition, depression, Alzheimer's disease, and stroke. The focus this review is elucidate highlight CNS diseases, with aim identifying potential risks arise from low level (variant or inhibitor) practice.

Language: Английский

---

Association of proprotein convertase subtilisin/kexin type 9 protein and oxidative stress indicators in women with preeclampsia: A case-control study

International Journal of Reproductive BioMedicine (IJRM), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 21, 2023

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) protein is one of the factors associated with oxidative stress and dyslipidemia disorders. Objective: This study aimed to evaluate lipid profile, PCSK9 levels, in preeclampsia. Materials Methods: case-control was conducted at Sina hospital Hamadan University Medical Sciences, Hamadan, Iran from August 2020-May 2021. The average maternal age included participants 30 yr preeclampsia healthy pregnant women. After clinical examination, fasting blood samples were collected, serum concentration, superoxide dismutase, glutathione peroxidase activities, levels determined by enzyme-linked immunosorbent assay. Total antioxidant capacity, total oxidant status, malondialdehyde manually. Results: 29.97 ± 4.75 31.23 5.85 yr, respectively. concentrations cholesterol, low-density lipoprotein cholesterol (LDL-C), PCSK9, higher group compared control (p < 0.02). activities lower cases 0.01). variable had a significant negative association parameters; however, positive observed between level parameters LDL-C. Conclusion: increased LDL-C women that increase risk endothelial damage hypertension Key words: Hypercholesterolemia, Oxidative stress, Preeclampsia.

Language: Английский

---

PCSK9 in extrahepatic tissues: What can we expect from its inhibition?

European Atherosclerosis Journal, Journal Year: 2023, Volume and Issue: 2(2), P. 35 - 43

Published: Aug. 31, 2023

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that belongs to the serine protease family and plays a key role in regulating low-density lipoprotein cholesterol (LDL-C) levels blood. PCSK9 binds LDL receptor (LDLR), targeting it for degradation, resulting increase circulating LDL-C levels. Loss-of-function mutations gene are associated with lower cardiovascular risk; contrast, gain-of-function cause of familial hypercholesterolaemia. The identification as pharmacological target led development inhibitors treatment To date, monoclonal antibodies evolocumab alirocumab (which plasma PCSK9) small-interfering RNA inclisiran targets hepatic mRNA) have been approved Although central levels, this protein also expressed other tissues, including brain, pancreas, heart, kidney, intestine adipose tissue. In extrahepatic functions both dependent independent LDLR not necessarily harmful. For reason, essential uncover any potentially harmful effects therapies inhibit PCSK9, beyond their known LDL-C-lowering CV risk-reducing effects.

Language: Английский

---

The Synergistic Trio of Metabolic Master Regulators Sustaining a Vicious Circle of Pathological Processes in Post-Traumatic Stress Disorder

Journal of Evolutionary Biochemistry and Physiology, Journal Year: 2024, Volume and Issue: 60(3), P. 988 - 1002

Published: May 1, 2024

Abstract Post-traumatic stress disorder (PTSD) is a maladaptive response to the exposure of an extraordinary-intensity stressor. The animal and human body responds any external challenges at systemic, organismal cellular levels. In stress-sensitive individuals, collaboration stress-implementing stress-limiting systems compromised, causing transformation behavior, cognitive abilities other functions central nervous system. It commonly accepted now that changes in abundance repertoire intestinal microbiota play important role pathogenesis PTSD. this regard, methods improving microflora are high on agenda. Analyzing literature data, we came conclusion metabolic, somatic mental health largely depends coordinated functioning key interdependent metabolic components: hepatobiliary system, and, as believe, state mast cells. Close scrutiny interplay these components will help identify new therapeutic targets most effective treat

Language: Английский

---

Transcriptome Profiling of Phenylalanine-Treated Human Neuronal Model: Spotlight on Neurite Impairment and Synaptic Connectivity

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10019 - 10019

Published: Sept. 18, 2024

Phenylketonuria (PKU) is the most common inherited disorder of amino acid metabolism, characterized by high levels phenylalanine (Phe) in blood and brain, leading to cognitive impairment without treatment. Nevertheless, Phe-mediated brain dysfunction not fully understood. The objective this study was address gene expression alterations due excessive Phe exposure human neuronal model provide molecular advances PKU pathophysiology. Hence, we performed NT2/D1 differentiation culture, and, for first time, used Phe-treated NT2-derived neurons (NT2/N) as a novel impairment. NT2/N were treated with 1.25 mM, 2.5 5 10 30 mM subjected whole-mRNA short-read sequencing. Differentially expressed genes (DEGs) analyzed enrichment analysis performed. Under three different concentrations (2.5 mM), DEGs pointed PREX1, LRP4, CDC42BPG, GPR50, PRMT8, RASGRF2, CDH6 genes, placing them context time. Enriched processes included dendrite axon impairment, synaptic transmission, membrane assembly. In contrast these groups, treatment group clearly represented neurotoxicity Phe, exhibiting apoptotic pathways. conclusion, established outlined Phe-induced changes resulting neurite altered connectivity.

Language: Английский

---

Synergic Trio of Metabolic Regulators Supporting the Vicious Circle of Pathological Processes in Post-Traumatic Stress Disorder

Российский физиологический журнал им  И  М  Сеченова, Journal Year: 2024, Volume and Issue: 110(5), P. 704 - 722

Published: Oct. 19, 2024

Post-traumatic stress disorder (PTSD) is a maladaptive response to exposure of extreme intensity stressor. The body animals and humans reacts at the systemic cellular levels, as with any external challenges. Disorder collective work stress-realizing stress-limiting systems causes transformation behavior, cognitive abilities other functions central nervous system in stress-sensitive individuals. Currently, it has been proven that pathogenesis PTSD, an important place occupied by changes number composition intestinal microbiota. In this regard, methods improving microflora are being considered. Analyzing data Russian foreign researchers, authors came conclusion, metabolic, somatic mental health largely depends on coordinated functioning main interdependent components metabolism: hepatobiliary system, microbiota and, according authors, state mast cells. A close study interaction these will allow us identify new therapeutic targets most effective treating PTSD.

Language: Английский

---