Production of human entorhinal stellate cell-like cells by forward programming shows an important role of Foxp1 in reprogramming

Bergmann, Tobias B.; Liu, Yong; Skov, Jonathan; Mogus, Leo; Lee, Julie; Pfisterer, Ulrich; Handfield, Louis-François; Asenjo-Martinez, Andrea; Lisa-Vargas, Irene; Seemann, Stefan E.; Lee, Jimmy Tsz Hang; Patikas, Nikolaos; Kornum, Birgitte Rahbek; Denham, Mark; Hyttel, Poul; Gorodkin, Jan; Pers, Tune H.; Hemberg, Martin; Khodosevich, Konstantin; Hall, Vanessa Jane

doi:10.3389/fcell.2022.976549

Cited by 2 publications

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“…In both cases, it is pertinent to ask whether major causative effects of these alleles are located within the neurons themselves. Conditional on the availability of human neuronal cell cultures in which neurons express a phenotype very similar to Re + ECLII neurons [42], the model can be used to predict the outcome of a cell culture experiment in which cells carrying ApoE ϵ 4/ ϵ 4, ApoE ϵ 3/ ϵ 3 and COLBOS genotypes are exposed to a substantially enhanced intracellular level of A β .…”

Section: Resultsmentioning

confidence: 99%

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Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Kobro-Flatmoen,

Omholt

2023

Preprint

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It was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer’s disease (AD)), the glycoprotein reelin and intracellular amyloid-β(Aβ) engage in a direct protein–protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric Aβin the onset of AD. If reelin functions as a sink for intracellular Aβand if the binding to reelin makes Aβphysiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric Aβ. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of Aβthan neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of Aβin ECLII neurons may in a senescent Aβ-inducing physiology predispose these neurons to initiate AD development.Author summaryAmyloid-βis a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimer’s disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid-βand reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimer’s disease. If intracellular amyloid-β, which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid-β. Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimer’s disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid-βproduction capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Kobro-Flatmoen,

Omholt

2023

Preprint

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The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer’s Disease

Bendtsen

Hall

2023

Cells

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Modeling Alzheimer’s disease (AD) using human-induced pluripotent stem cells (iPSCs) is a field now spanning 15 years. Developments in the field have shown a shift in using simple 2D cortical neuron models to more advanced tri-cultures and 3D cerebral organoids that recapitulate more features of the disease. This is largely due to development and optimization of new cell protocols. In this review, we highlight recent major breakthroughs in the AD field and the implications this has in modeling AD using iPSCs (AD-iPSCs). To date, AD-iPSCs have been largely used to recapitulate and study impaired amyloid precursor protein (APP) processing and tau phosphorylation in both familial and sporadic AD. AD-iPSCs have also been studied for varying neuronal and glial dysfunctions. Moreover, they have been useful for discovering new molecular mechanisms, such as identifying proteins that bridge APP processing with tau phosphorylation and for identifying molecular pathways that bridge APP processing dysfunction with impaired cholesterol biosynthesis. Perhaps the greatest use of AD-iPSCs has been in discovering compounds via drug screening, that reduce amyloid beta (Aβ) in neurons, such as the anti-inflammatory compound, cromolyn, and antiparasitic drugs, avermectins. In addition, high content screening using AD-iPSCs has led to the identification of statins that can reduce levels of phosphorylated tau (p-Tau) in neurons. Some of these compounds have made it through to testing in human clinical trials. Improvements in omic technologies including single cell RNA sequencing and proteomics as well as advances in production of iPSC-cerebral organoids and tri-cultures is likely to result in the further discovery of new drugs and treatments for AD. Some caveats remain in the field, including, long experimental conditions to create mature neurons, high costs of media that limit research capabilities, and a lack of reproducibility using current iPSC-cerebral organoid protocols. Despite these current limitations, AD-iPSCs remain an excellent cellular model for studying AD mechanisms and for drug discovery.

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Production of human entorhinal stellate cell-like cells by forward programming shows an important role of Foxp1 in reprogramming

Cited by 2 publications

References 92 publications

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer’s Disease

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