Therapeutic potential of mesenchymal stem cells on cholesterol homeostasis‐associated genes in AD‐like rats DOI Open Access
Mehrnaz Karimi Darabi, Arash Rafeeinia, Seyedeh Pardis Pezeshki

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(1)

Published: Jan. 3, 2025

Abstract Cholesterol is vital for nerve processes. Changes in cholesterol homeostasis lead to neurodegeneration and Alzheimer's disease (AD). In recent years, extensive research has confirmed the influential role of adipose tissue mesenchymal stem cells (MSCs) managing AD. The present study aims investigate a new approach concerning AD by MSCs with particular reference pathway its regulatory miRNAs an AD‐like rat model. Three groups 24 male Wistar rats have been divided: healthy (control), (AD), that received (AD + MSC). level was measured using GC‐mass technique. mRNA expression levels 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR), apolipoprotein E (APOE), ATP‐binding cassette transporter A1 (ABCA1), CYP46A1 genes, as well their regulating miRNAs, were assessed real‐time polymerase chain reaction (RT‐PCR) western blotting techniques, respectively. Intraventricular transplantation improved behavioral disorders decreased count Aβ plaques brain tissue. Transplantation these also led significant decrease HMGCR, ApoE, ABCA1 remarkable increase mRNAs protein expression. These considerably changed microRNAs genes. results indicated examined could be used promising biomarkers management. Additionally, potential therapeutic improving targeted related genes established.

Language: Английский

Lipid nanoparticles for nucleic acid delivery: Current perspectives DOI
Eleni Samaridou, James Heyes, Peter Lutwyche

et al.

Advanced Drug Delivery Reviews, Journal Year: 2020, Volume and Issue: 154-155, P. 37 - 63

Published: Jan. 1, 2020

Language: Английский

Citations

440
APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics DOI Creative Commons
Mohammed Amir Husain, Benoît Laurent, Mélanie Plourde

et al.

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Feb. 17, 2021

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD the APOE gene coding apolipoprotein E (apoE). Humans have three versions of gene: ε2, ε3, ε4 allele. Carrying allele an while carrying ε2 protective. ApoE component lipoprotein particles in plasma at periphery, as well cerebrospinal fluid (CSF) interstitial (ISF) brain parenchyma central nervous system (CNS). major lipid transporter that plays pivotal role development, maintenance, repair CNS, regulates multiple important signaling pathways. This review will focus on critical apoE pathogenesis some currently apoE-based therapeutics developed treatment AD.

Language: Английский

Citations

224
ApoE Lipidation as a Therapeutic Target in Alzheimer’s Disease DOI Open Access
Maria Fe Lanfranco, Christi Anne S. Ng, G. William Rebeck

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(17), P. 6336 - 6336

Published: Sept. 1, 2020

Apolipoprotein E (APOE) is the major cholesterol carrier in brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance degradation amyloid β (Aβ) neuroinflammation. In humans, APOE gene has three common allelic variants, termed E2, E3, E4. APOE4 considered strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE2 neuroprotective. To perform its functions, apoE must be secreted properly lipidated, a process influenced by structural differences associated with isoforms. Here we highlight importance lipidated as well APOE-lipidation targeted therapeutic approaches that have potential to correct or prevent neurodegeneration. Many these been validated using diverse animal models. Overall, there great improve state goal ameliorating APOE-associated central nervous system impairments.

Language: Английский

Citations

140
Oxidative stress and regeneration DOI
Morana Jaganjac, Lidija Milković, Neven Žarković

et al.

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 181, P. 154 - 165

Published: Feb. 8, 2022

Language: Английский

Citations

105
Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials DOI Creative Commons
Jifei Miao,

Haixia Ma,

Yang Yang

et al.

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: June 15, 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregation in the brain. Recent studies have revealed critical role of microglia AD pathogenesis. This review provides comprehensive summary current understanding microglial involvement AD, focusing on genetic determinants, phenotypic state, phagocytic capacity, neuroinflammatory response, and impact synaptic plasticity neuronal regulation. Furthermore, recent developments drug discovery targeting are reviewed, highlighting potential avenues for therapeutic intervention. emphasizes essential insights into treatments.

Language: Английский

Citations

91
Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma DOI Creative Commons
Cristian Ruiz-Moreno, Sergio Marco Salas, Erik Samuelsson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 27, 2022

SUMMARY Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity cell states dynamic changes in GB. Large-scale data integration can help uncover unexplored tumor pathobiology. Here, we resolved composition milieu created cellular map GB (‘GBmap’), curated resource that harmonizes 26 datasets gathering 240 patients spanning over 1.1 million cells. We showcase applications our for reference mapping, transfer learning, biological discoveries. Our results sources pro-angiogenic signaling multifaceted role mesenchymal-like cancer Reconstructing architecture using spatially transcriptomics unveiled high level well-structured neoplastic niches. The GBmap represents framework allows streamlined interpretation new provides platform exploratory analysis, hypothesis generation testing.

Language: Английский

Citations

84
Apolipoprotein E in lipid metabolism and neurodegenerative disease DOI Creative Commons
Linda Yang, Zachary M. March, Roxan A. Stephenson

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2023, Volume and Issue: 34(8), P. 430 - 445

Published: June 24, 2023

Dysregulation of lipid metabolism has emerged as a central component many neurodegenerative diseases. Variants the transport protein, apolipoprotein E (APOE), modulate risk and resilience in several diseases including late-onset Alzheimer's disease (LOAD). Allelic variants gene, APOE, alter cells tissues have been broadly associated with other cellular systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to disease-related phenotypes consequently, attenuate impart multiple We review molecular, cellular, tissue-level alterations that arise from different APOE isoforms. These changes could help elucidate mechanisms tune resilience.

Language: Английский

Citations

75
Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation DOI
Maria Fe Lanfranco, Jordy Sepulveda,

Gregory Kopetsky

et al.

Glia, Journal Year: 2021, Volume and Issue: 69(6), P. 1478 - 1493

Published: Feb. 8, 2021

Abstract Neuroinflammation is a common feature in neurodegenerative diseases, modulated by the Alzheimer's disease risk factor, apolipoprotein E ( APOE ). In brain, apoE protein synthesized astrocytes and microglia. We examined primary cultures of microglia from human (E2 , E3 E4) targeted‐replacement mice. Astrocytes secreted two species apoE, whereas cellular consisted only one. Both forms astrocytic were bound during glycoprotein isolation, enzymatic removal glycans produced convergence to single form; thus, astrocyte‐secreted are differentially glycosylated. Microglia released while forms; one treated glia with either endogenous (TNFα) or exogenous (LPS) pro‐inflammatory stimuli. While LPS had no effect on APOE2 APOE3 increased release apoE; APOE4 showed effect. higher baseline secretion TNFα compared treatment reduced expression astrocytes. The patterns not affected inflammation. No changes mRNA observed after both treatments. Together, our data demonstrate that express secrete glycosylated deficient immunomodulation .

Language: Английский

Citations

100
Culture Variabilities of Human iPSC-Derived Cerebral Organoids Are a Major Issue for the Modelling of Phenotypes Observed in Alzheimer’s Disease DOI
Damián Hernández, Louise Rooney, Maciej Daniszewski

et al.

Stem Cell Reviews and Reports, Journal Year: 2021, Volume and Issue: 18(2), P. 718 - 731

Published: March 16, 2021

Language: Английский

Citations

65
Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease DOI
Yann Le Guen, Michaël E. Belloy,

Benjamin Grenier‐Boley

et al.

JAMA Neurology, Journal Year: 2022, Volume and Issue: 79(7), P. 652 - 652

Published: May 31, 2022

The APOE ε2 and ε4 alleles are the strongest protective risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, mechanisms linking to AD-particularly apoE protein's role in AD pathogenesis how this is affected by variants-remain poorly understood. Identifying missense addition could provide critical new insights, but given low frequency of additional variants, cohorts have previously been too small interrogate question robustly.To determine whether rare on associated with risk.Association case-control status was tested a sequenced discovery sample (stage 1) followed up several microarray imputed as well UK Biobank whole-exome sequencing resource using proxy-AD phenotype (stages 2 3). This study combined case-control, family-based, population-based, longitudinal AD-related that recruited referred volunteer participants. Stage 1 included 37 409 nonunique participants European or admixed ancestry, 11 868 individuals 934 controls passing analysis inclusion criteria. In stages 3, 475 473 were considered across 8 cohorts, which 84 513 328 372 passed Selection criteria cohort specific, performed posteriori who genotyped. Among available genotypes, 76 195 excluded. All data retrieved between September 2015 November 2021 analyzed April 2021.In primary analyses, risk each variant estimated, appropriate, either linear mixed-model regression logistic regression. secondary associations estimated age at onset conversion competing-risk regression.A total 544 384 analysis; 312 476 (57.4%) female, mean (SD; range) 64.9 (15.2; 40-110) years. Two 2-fold 3-fold decreased risk: (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) ε3 (V236E) 0.37; 0.25-0.56; 1.9 10-6). Additionally, cumulative incidence carriers these found grow more slowly compared noncarriers.In association study, novel identified: R251G always coinherited gene, mitigates ε4-associated risk. effect V236E variant, also confirmed. location confirms carboxyl-terminal portion plays an important pathogenesis. large reductions reported here suggest protein chemistry functional assays should be pursued, they potential guide drug development targeting APOE.

Language: Английский

Citations

56