Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery

Oikari, Lotta E.; Pandit, Rucha; Stewart, Romal; Cuní-López, Carla; Quek, Hazel; Sutharsan, Ratneswary; Rantanen, Laura M.; Oksanen, Markku; Lehtonen, Šárka; Boer, Carmela Maria De; Polo, José M.; Götz, Jürgen; Koistinaho, Jari; White, Anthony R.

doi:10.1016/j.stemcr.2020.03.011

Cited by 70 publications

(169 citation statements)

References 51 publications

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“…Several studies have described the defects in iPSC-derived ECs with the PS1 mutation, a genetic risk factor for familial AD. Impaired barrier function resulting from downregulated TJ protein expression, reduced drug efflux pump activity, and glucose uptake was reported in these studies [ 221 , 255 , 256 , 257 ]. In addition, impairment of the mitochondrial membrane potentials and autophagy were also discovered in PS1 mutation ECs [ 257 ].…”

Section: Ipsc–bbb Models Of Neurodegenerative Diseasesmentioning

confidence: 95%

“…Studies have already shown that expression levels of transporters such as P-gp 1 are downregulated in AD patients. The transwell can provide evidence of the functional degradation of transporters, other than by measuring gene expression levels [ 220 , 221 ]. The transwell model has some limitations as well.…”

Section: Human-induced Pluripotent Stem Cells In Blood–brain Barrier Modelingmentioning

confidence: 99%

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Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

Sonninen

Peltonen

et al. 2021

IJMS

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The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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Section: Ipsc–bbb Models Of Neurodegenerative Diseasesmentioning

confidence: 95%

Section: Human-induced Pluripotent Stem Cells In Blood–brain Barrier Modelingmentioning

confidence: 99%

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

Sonninen

Peltonen

et al. 2021

IJMS

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“…RNA and cDNA were prepared as previously described ( 39 ). Total RNA was extracted using a Direct-zol RNA Miniprep kit (Integrated Sciences, Australia) as per manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

3D models of Alzheimer’s disease patient microglia recapitulate disease phenotype and show differential drug responses compared to 2D

Cuní-López

Quek

Oikari

et al. 2021

Preprint

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Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brain’s resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no current in vitro model system that faithfully recapitulates patient-specific microglial characteristics. To address this shortcoming, we developed novel 3D models of monocyte-derived microglia-like cells (MDMi) from AD patients. MDMi in 3D exhibited mature microglial features, including a highly branched morphology and enhanced bonafide microglial marker expression compared to 2D. Moreover, AD MDMi in 3D co-cultures with neuro-glial cells showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-β. Drug screening assays in 3D AD MDMi revealed different cytokine responses compared to 2D. Our study demonstrates disease- and drug-specific responses in 3D MDMi models that are not apparent in 2D and presents a new 3D platform for more effective and personalised drug testing.

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“…BMECs have unique expression profile, energy metabolism, high mitochondrial content, and secretory activity which changes upon stimulation of cerebral angiogenesis (developmental, activity-induced, or restorative) as well as in neurodegeneration [ 101 , 102 ]. BMECs within the NVU/BBB are characterized by specific properties distinct from endothelial cells in other tissues.…”

Section: Mitochondrial Dysfunction and Nvu/bbb Impairment In Alzheimer’s Type Neurodegenerationmentioning

confidence: 99%

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

Салмина

Kharitonova

Gorina

et al. 2021

IJMS

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Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood–brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer’s disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer’s disease.

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Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery

Cited by 70 publications

References 51 publications

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

3D models of Alzheimer’s disease patient microglia recapitulate disease phenotype and show differential drug responses compared to 2D

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

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