Analysis of transporter activity in an Alzheimer’s disease blood-brain barrier cell model DOI Creative Commons
J. Chaves

Published: Jan. 1, 2024

This thesis investigates blood-brain barrier (BBB) transporter changes in Alzheimer’s disease (AD) using stem cell models. It reviews BBB function AD and successfully differentiates cells into components. Findings suggest dysregulation of certain transporters AD, potentially contributing to onset. study also explores inflammation's impact on expression suggests non-invasive modulation as a therapeutic avenue. Additionally, it inflammatory responses SARS-CoV-2 spike protein exposure cell-derived cells, indicating potential implications for COVID-19 manifestation.

Language: Английский

Blood-brain barrier transporters: An overview of function, dysfunction in Alzheimer's disease and strategies for treatment DOI Creative Commons

Juliana C.S. Chaves,

Samantha J. Dando, Anthony R. White

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1870(2), P. 166967 - 166967

Published: Nov. 24, 2023

Language: Английский

Citations

9
ZNF787 and HDAC1 Mediate Blood–Brain Barrier Permeability in an In Vitro Model of Alzheimer’s Disease Microenvironment DOI
Lu Zhang,

Baicheng Zhu,

Xinxin Zhou

et al.

Neurotoxicity Research, Journal Year: 2024, Volume and Issue: 42(1)

Published: Feb. 1, 2024

Language: Английский

Citations

2
Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound DOI Creative Commons

Juliana C.S. Chaves,

Joanna M. Wasielewska, Carla Cuní‐López

et al.

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 21(1), P. e00299 - e00299

Published: Dec. 19, 2023

The blood-brain barrier (BBB) has a key function in maintaining homeostasis the brain, partly modulated by transporters, which are highly expressed brain endothelial cells (BECs). Transporters mediate uptake or efflux of compounds to and from they can also challenge delivery drugs for treatment Alzheimer's disease (AD). Currently there is limited understanding changes BBB transporters AD. To investigate this, we generated endothelial-like (iBECs) induced pluripotent stem (iPSCs) with familial AD (FAD) Presenilin 1 (PSEN1) mutation identified AD-specific differences transporter expression compared control (ctrl) iBECs. We first characterized levels 12 AD-, Ctrl-, isogenic (PSEN1 corrected) iBECs identify any specific differences. then exposed focused ultrasound (FUS) absence (FUS

Language: Английский

Citations

4
Progress and preclinical application status of ultrasound microbubbles DOI

Qiaoying Hu,

Yu Zhang,

Lu Fu

et al.

Journal of Drug Delivery Science and Technology, Journal Year: 2024, Volume and Issue: 92, P. 105312 - 105312

Published: Jan. 4, 2024

Language: Английский

Citations

1
A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery DOI Open Access
Joanna M. Wasielewska, Mauricio Castro Cabral-da-Silva, Martina Pecoraro

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 27, 2024

Abstract Background Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development the non-invasive therapeutic access to motor cortex currently limited by presence of blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS +MB ) an emerging technology that was successfully used patients temporarily open cortical BBB. However, FUS -mediated delivery across patients’ BBB has not yet been reported. Similarly, effects on human cells remain unexplored. Methods Here we established first -compatible, fully-human patient-cell-derived model based induced brain endothelial-like (iBECs) study anti-TDP-43 antibody bioeffects vitro . Results Generated iBECs recapitulated disease-specific hallmarks pathology, including changes integrity, permeability TDP-43 proteinopathy. Our results also identified differences between sporadic familial ( C9orf72 expansion carrying) reflecting patient heterogeneity associated disease subgroups. Studies these models revealed successful iBEC monolayer opening lack adverse cellular This accompanied molecular expression tight adherens junction markers, transporter inflammatory mediators, generating transient specific responses. Additionally, demonstrated increase (2.7-fold) (1.9-fold) providing proof-of-concept evidence can be enhance large molecule therapeutics model. Conclusions Together, our describes characterisation responses provides platform for screening

Language: Английский

Citations

1
Differential Cytokine Responses of APOE3 and APOE4 Blood–brain Barrier Cell Types to SARS-CoV-2 Spike Proteins DOI

Juliana C.S. Chaves,

Laura A. Milton, Romal Stewart

et al.

Journal of Neuroimmune Pharmacology, Journal Year: 2024, Volume and Issue: 19(1)

Published: May 21, 2024

Language: Английский

Citations

1
Alzheimer’s disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound DOI Creative Commons

Juliana C.S. Chaves,

Joanna M. Wasielewska, Carla Cuní‐López

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: March 1, 2023

Abstract Background The blood-brain barrier (BBB) has a major role in maintaining homeostasis of the brain. primary function BBB is regulating entry molecules from blood to brain while protecting potentially harmful endogenous and exogenous substances. Transporters expressed endothelial cells (BECs) mediate uptake or efflux compounds they can also challenge delivery drugs into for treatment disorders including Alzheimer’s disease (AD). AD most common form dementia, however, currently there limited understanding transporters AD-related dysfunction. Methods We investigated differences transporter expression activity endothelial-like (iBECs) differentiated induced pluripotent stem (iPSCs) obtained people carrying familial Presenilin 1 ( PSEN1 ) mutation exon 9 deletion; AD-iBECs), healthy controls (Ctrl-iBECs), isogenic 9-corrected lines COR -iBECs). first characterized levels 12 AD-, Ctrl-, iBECs identify any specific differences. then exposed focused ultrasound, absence (FUS only presence microbubbles +MB ), examine whether key be modulated by therapeutic novel technique allowing transient opening. Results Our results identified between AD-iBECs control iBECs, suggesting disease-specific effects on expression. Additionally, our demonstrated FUS have potential modulate activity. Interestingly, significantly reduced PGP-mediated Aβ accumulation following , an effect not seen Ctrl-iBECs, disease-related Conclusions findings demonstrate that mutant possess phenotypical compared corrected unrelated function. we show functional having implications drug penetration amyloid clearance. These highlight differential responses patient treatment, with patient-derived models likely providing important tool modelling FUS.

Language: Английский

Citations

3
A patient-derived blood-brain barrier model for screening copper bis(thiosemicarbazone) complexes as potential therapeutics in Alzheimer’s disease DOI Creative Commons
Joanna M. Wasielewska, Kathryn Szostak,

Lachlan E. McInnes

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 21, 2023

Abstract Alzheimer’s disease (AD) is the most prevalent cause of dementia characterised by progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD, however, development effective anti-neuroinflammatory compounds often hindered their limited blood-brain barrier (BBB) permeability. Consequently, there an urgent need for accurate, preclinical AD patient-specific BBB models facilitate early identification immunomodulatory drugs capable efficiently crossing human BBB. This study presents unique approach drug permeability screening as it utilises familial patient-derived induced brain endothelial-like cells (iBEC)-based model, which exhibits increased relevance and serves improved assessment tool when compared traditionally employed in vitro models. To demonstrate its utility small molecule candidate platform, we investigated effects Cu II (atsm) library novel metal bis(thiosemicarbazone) complexes – class exhibiting potential neurodegenerative disorders. By evaluating toxicity, cellular accumulation those iBEC, have identified (dtsm) emerging with enhanced transport across Furthermore, developed multiplex where iBEC were combined immune modulators TNFα IFNγ establish model representing characteristic neuroinflammatory phenotype at patient’s Here observed that treatment not only reduced expression proinflammatory cytokine genes but also reversed detrimental IFNψ on integrity function monolayer. suggests pathway through copper may exert neurotherapeutic mitigating related impairment. Together, presented provides easily scalable platform candidates. Its translational makes valuable advancing metal-based aimed modulating AD. Graphical abstract

Language: Английский

Citations

2
Increased tau expression in theAPOE4blood-brain barrier model is associated with reduced anti-tau therapeutic antibody deliveryin vitro DOI Creative Commons
Joanna M. Wasielewska, Rinie Bajracharya, Rebecca L. Johnston

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 25, 2023

Abstract Tau protein is a critical driver of neurodegeneration and an important drug target in Alzheimer’s disease (AD). Tau-specific immunotherapy has emerged as promising treatment strategy for AD, however the therapeutic efficacy anti-tau antibodies may be limited by their insufficient delivery across blood-brain barrier (BBB). The apolipoprotein E4 allele ( APOE4 ) strongest genetic risk factor sporadic AD known to influence tau-mediated neurodegeneration. Interestingly, both tau have been implicated cerebrovascular pathology observed AD. Yet, crosstalk between at level BBB its consequences immunotherapeutics delivery, remain poorly understood. Here, we utilised APOE3 - -carrying human iPSC-derived induced brain endothelial-like cells (iBECs) model, determined levels endogenous iBECs, explored transport two novel monoclonal antibodies, RNF5 RN2N, vitro barrier. Our results demonstrate that MAPT gene transcription, phosphorylation are increased iBECs -related manner associated with reduced iBEC monolayer integrity permeability biologically inert fluorescent tracers. Additionally, elevated intracellular were accompanied passive through monolayer, which could improved application focused ultrasound microbubble drug-delivery technology. Together, our study illustrates new role potential implications dysfunction antibody delivery.

Language: Английский

Citations

2
Development of an In Vitro Model to Study Mechanisms of Ultrasound-Targeted Microbubble Cavitation–Mediated Blood–Brain Barrier Opening DOI Creative Commons
Grace E. Conway, Anurag N. Paranjape, Xucai Chen

et al.

Ultrasound in Medicine & Biology, Journal Year: 2023, Volume and Issue: 50(3), P. 425 - 433

Published: Dec. 29, 2023

Language: Английский

Citations

2