Modeling Alzheimer’s Disease Using Human Brain Organoids

Karmirian, Karina; Holubiec, Mariana; Goto‐Silva, Livia; Bessone, Iván Fernandez; Vitória, Gabriela; Mello, Beatriz; Alloatti, Matías; Vanderborght, Bart; Falzone, Tomás L.; Rehen, Stevens

doi:10.1007/978-1-0716-2655-9_7

Cited by 9 publications

(3 citation statements)

References 33 publications

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“…Since the genetic background of the donor is retained during cell reprogramming, hiPSCs are an excellent source to analyze the effect of disease-inducing mutations in the CNS cell types such as neurons, glial cells, pericytes, brain microvascular endothelial cells during the disease pathogenesis [ 227 , 228 ]. In addition to the existing efficient monolayer differentiation protocols [ 229 , 230 , 231 ], more complex multicellular and three-dimensional (3D) organoids have been developed to capture disease-relevant multicellular interactions and closely examine human neuronal development and human brain disease pathogenesis in tissue culture [ 19 , 20 ]. Several patient-specific iPSC lines have been generated modeling and treating various neurodegenerative diseases, including PD, AD, ALS, TBI, ME/CFS, and GWI [ 232 , 233 , 234 , 235 , 236 , 237 ].…”

Section: The Use Of Ipsc-derived Cells In Neuroinflammatory Disease P...mentioning

confidence: 99%

“…Human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, microglia, endothelial cells, and pericytes are currently used for many diseases modeling drug discovery for various neuroinflammatory disorders [ 18 ]. These human hiPSC-derived cells are used for various co-culture systems, brain organoids, and neurovascular unit cultures [ 19 , 20 ]. There are no disease-modifying treatment options currently available for neuroinflammatory disorders and are treated symptomatically.…”

Section: Introductionmentioning

confidence: 99%

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Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood–brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

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Section: The Use Of Ipsc-derived Cells In Neuroinflammatory Disease P...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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“…TG mice expressing non-mutant human tau isoforms exhibit tau pathology, including hyperphophorylated tau accumulation and cognitive deficits [5,6]. Evidence from in vitro studies utilizing two-and three-dimensional models has furthered our understanding of the AD pathology [7][8][9][10].…”

Section: Introduction 1alzheimer's Diseasementioning

confidence: 99%

A Combination of Heavy Metals and Intracellular Pathway Modulators Induces Alzheimer Disease-like Pathologies in Organotypic Brain Slices

Korde,

Humpel

2024

Biomolecules

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFT). Modelling aspects of AD is challenging due to its complex multifactorial etiology and pathology. The present study aims to establish a cost-effective and rapid method to model the two primary pathologies in organotypic brain slices. Coronal hippocampal brain slices (150 µm) were generated from postnatal (day 8–10) C57BL6 wild-type mice and cultured for 9 weeks. Collagen hydrogels containing either an empty load or a mixture of human Aβ42 and P301S aggregated tau were applied to the slices. The media was further supplemented with various intracellular pathway modulators or heavy metals to augment the appearance of Aβ plaques and tau NFTs, as assessed by immunohistochemistry. Immunoreactivity for Aβ and tau was significantly increased in the ventral areas in slices with a mixture of human Aβ42 and P301S aggregated tau compared to slices with empty hydrogels. Aβ plaque- and tau NFT-like pathologies could be induced independently in slices. Heavy metals (aluminum, lead, cadmium) potently augmented Aβ plaque-like pathology, which developed intracellularly prior to cell death. Intracellular pathway modulators (scopolamine, wortmannin, MHY1485) significantly boosted tau NFT-like pathologies. A combination of nanomolar concentrations of scopolamine, wortmannin, MHY1485, lead, and cadmium in the media strongly increased Aβ plaque- and tau NFT-like immunoreactivity in ventral areas compared to the slices with non-supplemented media. The results highlight that we could harness the potential of the collagen hydrogel-based spreading of human Aβ42 and P301S aggregated tau, along with pharmacological manipulation, to produce pathologies relevant to AD. The results offer a novel ex vivo organotypic slice model to investigate AD pathologies with potential applications for screening drugs or therapies in the future.

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