Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure

Advanced Science, Journal Year: 2021, Volume and Issue: 8(18)

Published: Aug. 2, 2021

Alzheimer's disease (AD) is a progressive neurodegenerative with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies failed. Possible reasons high failure rate include incomplete understanding of complex pathophysiology AD, especially sporadic AD (sAD), and species difference between humans animal models used preclinical studies. In this study, sAD modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because blood-brain barrier (BBB) leakage well-known risk factor organoids are exposed serum mimic exposure consequence BBB breakdown patient brains. The serum-exposed able recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, impaired neural network. Serum increases Aβ p-Tau levels through inducing beta-secretase 1 (BACE) glycogen synthase kinase-3 alpha / (GSK3α/β) levels, respectively. addition, single-cell transcriptomic analysis reveals that reduced function both neurons astrocytes immune response astrocytes. organoid-based model established study can provide powerful platform mechanistic therapeutic future.

Language: Английский

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Organoids: The current status and biomedical applications

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 17, 2023

Organoids are three-dimensional (3D) miniaturized versions of organs or tissues that derived from cells with stem potential and can self-organize differentiate into 3D cell masses, recapitulating the morphology functions their in vivo counterparts. Organoid culture is an emerging technology, organoids various tissues, such as brain, lung, heart, liver, kidney, have been generated. Compared traditional bidimensional culture, organoid systems unique advantage conserving parental gene expression mutation characteristics, well long-term maintenance function biological characteristics vitro. All these features open up new opportunities for drug discovery, large-scale screening, precision medicine. Another major application disease modeling, especially hereditary diseases difficult to model vitro modeled by combining genome editing technologies. Herein, we introduce development current advances technology field. We focus on applications basic biology clinical research, also highlight limitations future perspectives. hope this review provide a valuable reference developments organoids.

Language: Английский

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Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

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

Published: April 26, 2024

The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable genetic engineering, can be differentiated into most somatic types. been widely applied model human development diseases, perform drug screening, develop therapies. In this review, we outline key developments iPSC field highlight immense versatility of modeling therapeutic applications. We begin by discussing pivotal discoveries that revealed potential a nucleus reprogramming led successful generation iPSCs. consider molecular mechanisms dynamics as well numerous methods available induce pluripotency. Subsequently, discuss various iPSC-based cellular models, from mono-cultures single type complex three-dimensional organoids, how these models elucidate diseases. use examples neurological disorders, coronavirus disease 2019 (COVID-19), cancer diversity disease-specific phenotypes modeled using iPSC-derived cells. also used high-throughput screening toxicity studies. Finally, process developing autologous allogeneic therapies their alleviate

Language: Английский

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Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12046 - 12046

Published: July 27, 2023

Although historically, the traditional bidimensional in vitro cell system has been widely used research, providing much fundamental information regarding cellular functions and signaling pathways as well nuclear activities, simplicity of this does not fully reflect heterogeneity complexity vivo systems. From arises need to use animals for experimental research testing. Nevertheless, animal experimentation presents various aspects complexity, such ethical issues, which led Russell Burch 1959 formulate 3R (Replacement, Reduction, Refinement) principle, underlying urgent introduce non-animal-based methods research. Considering this, three-dimensional (3D) models emerged scientific community a bridge between models, allowing achievement differentiation while avoiding The purpose review is provide general overview most common establish 3D culture discuss their promising applications. Three-dimensional cultures have employed study both organ physiology diseases; moreover, they represent valuable tool studying many cancer. Finally, possibility using drug screening regenerative medicine paves way development new therapeutic opportunities diseases.

Language: Английский

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Neuropathogenesis-on-chips for neurodegenerative diseases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

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Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids: Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery

Annals of Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Objective Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP challenging due to the lack models reproducing its key pathological features. This study aimed model sporadic PSP‐Richardson's syndrome (PSP‐RS) using multi‐donor midbrain organoids (MOs). Methods The MOs were generated pooling induced pluripotent stem cells (iPSCs) from 4 patients with probable PSP‐RS compared them 3 healthy control (HC) subjects. We performed comprehensive analyses over 120 days assess neuronal death, reactive gliosis, accumulation 4R‐tau forms (pThr231, pSer396, pThr181, pSer202/pThr205 [AT8]) immunofluorescence microscopy Western blot. On day 90, immunohistochemical analysis pSer396 AT8 antibodies was conducted pathology. Results PSP‐derived showed progressive size reduction HC‐derived MOs, linked upregulated apoptosis‐related mRNA markers. Dopaminergic neuron degeneration marked decreased tyrosine hydroxylase (TH) increased neurofilament light chain (NfL). Immunofluorescence blot revealed all investigated peak at 90 days, along significant rise in GFAP‐positive MOs. Immunochemistry confirmed typical histological alterations, such as neurofibrillary tufted‐shaped astrocytes, absent organoids. Interpretation developed robust vitro molecular histologic features disease. result holds promise advancing basic clinical research PSP, paving way diagnosis identification novel therapeutic targets. ANN NEUROL 2025

Language: Английский

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Pushing the boundaries of brain organoids to study Alzheimer’s disease

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 659 - 672

Published: June 22, 2023

Progression of Alzheimer's disease (AD) entails deterioration or aberrant function multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell-cell interactions become dysregulated in AD requires novel human cell-based vitro platforms that could recapitulate the intricate cytoarchitecture diversity brain. Brain organoids (BOs) are 3D self-organizing tissues partially resemble architecture can AD-relevant pathology. In this review, we highlight versatile applications different types BOs model pathogenesis, including amyloid-β tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, other phenotypes, as well accelerate therapeutic development for AD.

Language: Английский

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Brain organoids are new tool for drug screening of neurological diseases

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 0(0), P. 0 - 0

Published: Jan. 1, 2023

At the level of in vitro drug screening, development a phenotypic analysis system with high-content screening at core provides strong platform to support high-throughput screening. There are few systematic reports on brain organoids, as new three-dimensional model, terms model stability, key fingerprint, and schemes, particularly regarding strategies for massive numbers traditional Chinese medicine monomers. This paper reviews organoids advantages over induced neurons or cells simulated diseases. The also highlights prospects from induction criteria schemes based characteristics application system.

Language: Английский

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Promoting Alzheimer’s disease research and therapy with stem cell technology

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 7, 2024

Abstract Background Alzheimer’s disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, decreased self-care. Current AD treatments aim relieve symptoms slow progression, but cure elusive due limited understanding the underlying mechanisms. Main content Stem cell technology has potential revolutionize research. With ability self-renew differentiate into various types, stem cells are valuable tools for modeling, drug screening, therapy. Recent advances have broadened our beyond deposition amyloidβ (Aβ) or tau proteins in encompass risk genes, immune system disorders, neuron–glia mis-communication, relying heavily on cell-derived models. These cell-based models (e.g., organoids microfluidic chips) simulate vivo pathological processes with extraordinary spatial temporal resolution. technologies alleviate pathology through pathways, including immunomodulation, replacement damaged neurons, neurotrophic support. In recent years, transplantation glial like oligodendrocytes infusion exosomes become hot research topics. Conclusion Although therapies face several challenges, such as extended culture time low differentiation efficiency, they still show considerable treatment likely preferred

Language: Английский

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Induced Pluripotent Stem Cells in Drug Discovery and Neurodegenerative Disease Modelling

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2392 - 2392

Published: Feb. 18, 2024

Induced pluripotent stem cells (iPSCs) are derived from reprogrammed adult somatic cells. These manipulated in vitro to express genes and factors essential for acquiring maintaining embryonic cell (ESC) properties. This technology is widely applied many fields, much attention has been given developing iPSC-based disease models validate drug discovery platforms study the pathophysiological molecular processes underlying onset. Especially neurological diseases, there a great need technological research, as these can be obtained each patient carry individual’s bulk of genetic mutations unique Moreover, iPSCs differentiate into multiple types. characteristics, since diseases affected by limited access injury sites, composed various types, complexity reproducing brain’s anatomy, challenges postmortem culture, ethical issues. Neurodegenerative strongly impact global health due their high incidence, symptom severity, lack effective therapies. Recently, analyses using specific, confirmed efficacy testing drugs. review summarizes advances iPSC used modelling testing, with primary focus on neurodegenerative including Parkinson’s Alzheimer’s diseases.

Language: Английский

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