Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain

Espuny-Camacho, Ira; Arranz, Amaia M.; Fiers, Mark; An, Shengli; Ando, Kunie; Munck, Sebastian; Bonnefont, Jérôme; Lambot, Laurie; Corthout, Nikky; Omodho, Lorna; Eynden, Elke Vanden; Radælli, Enrico; Tesseur, Ina; Wray, Selina; Ebneth, Andreas; Hardy, John; Leroy, Karelle; Brion, Jean Pierre; Vanderhaeghen, Pierre; Strooper, Bart De

doi:10.1016/j.neuron.2017.02.001

Cited by 203 publications

(185 citation statements)

References 59 publications

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“…Our most significant DMP resided in BNC1 (cg26429925; standardized regression coefficient = -0.75, p = 4.71E-06). Differential methylation of BNC1, which encodes a zinc finger protein basonuclein, has been previously found in frontal cortex of AD subjects compared with controls [31], and upregulation of BNC1 has been observed in a novel chimeric model of AD [32].…”

Section: Resultsmentioning

confidence: 85%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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Aim:The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging. DNA methylation (DNAm) changes have been linked with the pathophysiology of brain aging, Alzheimer's disease (AD) and other types of dementia [1,2]. Considering the relative stability of DNAm and the fact that it is directly modulated by both underlying genetic sequence and environmental exposures it appears as a promising peripheral biomarker for brain-related changes [3]. Peripheral changes in mRNA and proteins that are downstream of DNAm regulation further support this concept [4,5]. Studies have shown differences in blood DNAm when comparing AD subjects with controls [6], but interestingly when looking at specific genes there is little overlap between brain and blood DNAm changes in AD [7,8]. However, a good peripheral biomarker does not have to mirror disease-associated changes in the brain; it could also simply represent a peripheral response to central pathology. At present, there is limited data available on the potential utility of peripheral DNAm as a marker for cognitive decline before the onset of dementia. One study of patients with Type 2 diabetes mellitus who later developed presymptomatic dementia highlighted leukocyte DNAm changes that were comparable to changes identified in blood in AD patients and could thus potentially represent early markers of dementia [9]. Recently DNAm epigenetic clocks have been developed, which provide a measure of epigenetic age, based on DNAm levels at 353 CpG sites [10] and 71 CpG sites [11], respectively. A number of studies have utilized the epigenetic age in blood, based on the DNAm epigenetic clock, to show correlations with cognitive function, white matter hyperintensities (WMH), Parkinson's disease, Down syndrome and all-cause mortality [12][13][14][15][16].

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Section: Resultsmentioning

confidence: 85%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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“…However, none of the neurons die in culture, as seen in AD patients [8,92]. Recently, it was reported that healthy neurons from hiPSC degenerate if transplanted in PD model mouse brains, suggesting that amyloid plaques from the diseased environment are responsible for neural degeneration [93].…”

Section: Using Pscs For Modeling Neurovascular Diseasementioning

confidence: 99%

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Lauschke

Frederiksen

Hall

2017

Stem Cells and Development

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“…Recently a unique chimeric human-mouse model was developed by transplanting stem-cell-derived human cortical neurons into mouse brain. [194] Remarkably, the new mice showed that A β species generated in the brain can induce AD hallmarks, including tau hyperphosphorylation, neurite dystrophy, and cell death in non-manipulated human neurons. This study highlights the unmet need for engineering more physiologically relevant matrices that could fully recapitulate the natural ECM architecture and function.…”

Section: Designing Synthetic Matrices For Recapitulating the Extramentioning

confidence: 99%

Three‐Dimensional Models of the Human Brain Development and Diseases

Jorfi

D’Avanzo

Kim

et al. 2017

Adv Healthcare Materials

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Deciphering the human brain pathophysiology remains one of the greatest challenges of the 21st century. Neurological disorders represent a significant proportion of diseases burden; however, the complexity of the brain physiology makes it challenging to model its diseases. Simple in vitro models have been very useful for precise measurements in controled conditions. However, existing models are limited in their ability to replicate complex interactions between various cells in the brain. Studying human brain requires sophisticated models to reconstitute the tangled architecture and functions of brain cells. Recently, advances in the development of three-dimensional (3D) brain cell culture models have begun to recapitulate various aspects of the human brain physiology in vitro and replicate basic disease processes of Alzheimer’s disease, amyotrophic lateral sclerosis, and microcephaly. In this review, we discuss the progress, advantages, limitations, and future directions of 3D cell culture systems for modeling the human brain development and diseases.

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Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain

Cited by 203 publications

References 59 publications

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Three‐Dimensional Models of the Human Brain Development and Diseases

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