Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia.

Despite the central role attributed to neuroinflammation in the etiology and pathobiology of Alzheimer's disease (AD), the direct link between levels of inflammatory mediators in blood and cerebrospinal fluid (CSF) compartments, as well as their potential implications for AD diagnosis and progression, remains inconclusive. Moreover, there is debate on whether inflammation has a protective or detrimental effect on disease onset and progression. Indeed, distinct immunological mechanisms may govern protective and damaging effects at early and late stages, respectively.

Association of oxidative stress and inflammatory metabolites with Alzheimer's disease cerebrospinal fluid biomarkers in mild cognitive impairment.

Background: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects.

Scalable expansion of iPSC and their derivatives across multiple lineages.

Induced pluripotent stem cell (iPSC) technology enabled the production of pluripotent stem cell lines from somatic cells from a range of known genetic backgrounds. Their ability to differentiate and generate a wide variety of cell types has resulted in their use for various biomedical applications, including toxicity testing. Many of these iPSC lines are now registered in databases and stored in biobanks such as the European Bank for induced pluripotent Stem Cells (EBiSC), which can streamline the quality control and distribution of these individual lines.

EBiSC best practice: How to ensure optimal generation, qualification, and distribution of iPSC lines.

Disease-relevant human induced pluripotent stem cells (iPSCs) are generated worldwide for research purposes; however, without robust and practical ethical, legal, and quality standards, there is a high risk that their true potential will not be realized. Best practices for tissue procurement, iPSC reprogramming, day-to-day cultivation, quality control, and data management aligned with an ethical and legal framework must be included into daily operations to ensure their promise is maximized. Here we discuss key learning experiences from 7 years of operating the European Bank for induced Pluripotent Stem Cells (EBiSC) and recommend how to incorporate solutions into a daily management framework.

Development of a fully human assay combining NGN2-inducible neurons co-cultured with iPSC-derived astrocytes amenable for electrophysiological studies.

Neurogenin 2 encodes a neural-specific transcription factor (NGN2) able to drive neuronal fate on somatic and stem cells. NGN2 is expressed in neural progenitors within the developing central and peripheral nervous systems. Overexpression of NGN2 in human induced pluripotent stem cells (hiPSCs) or human embryonic stem cells has been shown to efficiently trigger conversion to neurons.

SOX9-induced Generation of Functional Astrocytes Supporting Neuronal Maturation in an All-human System.

Astrocytes, the main supportive cell type of the brain, show functional impairments upon ageing and in a broad spectrum of neurological disorders. Limited access to human astroglia for pre-clinical studies has been a major bottleneck delaying our understanding of their role in brain health and disease. We demonstrate here that functionally mature human astrocytes can be generated by SOX9 overexpression for 6 days in pluripotent stem cell (PSC)-derived neural progenitor cells.

Generation of a set of isogenic iPSC lines carrying all APOE genetic variants (Ɛ2/Ɛ3/Ɛ4) and knock-out for the study of APOE biology in health and disease.

APOE genotype is the strongest genetic risk factor for Alzheimer's Disease (AD). The low degree of homology between mouse and human APOE is a concerning issue in preclinical models currently used to study the role of this gene in AD pathophysiology. A key objective of ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project was to generate in vitro models that better recapitulate human APOE biology.

Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer's disease.

Background: Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD.

Methods: The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts.

CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ε4 carriers.

Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE.

Deploying human pluripotent stem cells to treat central nervous system disorders: facts, challenges and realising the potential.

Human pluripotent stem cells (hPSC) represent a unique opportunity to study fundamental biological processes in a human- and cell-specific setting. Its translational potential and the impact on human health makes this technology revolutionary. The possibility to generate stem cells from almost any somatic cell, and their capacity to be differentiated in virtually all cells of the body has been demonstrated extensively during the last decade of research.

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death.

Generation of a set of isogenic, gene-edited iPSC lines homozygous for all main APOE variants and an APOE knock-out line.

Alzheimer's disease (AD) is the most frequent neurodegenerative disease amongst the elderly. The SNPs rs429358 and rs7412 in the APOE gene are the most common risk factor for sporadic AD, and there are three different alleles commonly referred to as APOE-ε2, APOE-ε3 and APOE-ε4. Induced pluripotent stem cells (iPSCs) hold great promise to model AD as such cells can be differentiated in vitro to the required cell type.

Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes.

Tauopathies such as frontotemporal dementia (FTD) remain incurable to date, partially due to the lack of translational in vitro disease models. The MAPT gene, encoding the microtubule-associated protein tau, has been shown to play an important role in FTD pathogenesis. Therefore, we used zinc finger nucleases to introduce two MAPT mutations into healthy donor induced pluripotent stem cells (iPSCs).

Generation of a human induced pluripotent stem cell-based model for tauopathies combining three microtubule-associated protein TAU mutations which displays several phenotypes linked to neurodegeneration.

Introduction: Tauopathies are neurodegenerative diseases characterized by TAU protein-related pathology, including frontotemporal dementia and Alzheimer's disease among others. Mutant TAU animal models are available, but none of them faithfully recapitulates human pathology and are not suitable for drug screening.

Methods: To create a new in vitro tauopathy model, we generated a footprint-free triple MAPT-mutant human induced pluripotent stem cell line (N279K, P301L, and E10+16 mutations) using clustered regularly interspaced short palindromic repeats-FokI and piggyBac transposase technology.

Rapid establishment of the European Bank for induced Pluripotent Stem Cells (EBiSC) - the Hot Start experience.

A fast track "Hot Start" process was implemented to launch the European Bank for Induced Pluripotent Stem Cells (EBiSC) to provide early release of a range of established control and disease linked human induced pluripotent stem cell (hiPSC) lines. Established practice amongst consortium members was surveyed to arrive at harmonised and publically accessible Standard Operations Procedures (SOPs) for tissue procurement, bio-sample tracking, iPSC expansion, cryopreservation, qualification and distribution to the research community. These were implemented to create a quality managed foundational collection of lines and associated data made available for distribution.

LHX2 is necessary for the maintenance of optic identity and for the progression of optic morphogenesis.

Eye formation is regulated by a complex network of eye field transcription factors (EFTFs), including LIM-homeodomain gene LHX2. We disrupted LHX2 function at different stages during this process using a conditional knock-out strategy in mice. We find that LHX2 function is required in an ongoing fashion to maintain optic identity across multiple stages, from the formation of the optic vesicle to the differentiation of the neuroretina.

Dynamic expression of the p53 family members p63 and p73 in the mouse and human telencephalon during development and in adulthood.

p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and death of mammalian cells. They display high homology and may act in concert. The p73 gene is relevant for brain development, and p73-deficient mice display important malformations of the telencephalon.

Distribution patterns of estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood.

The expression of estrogen receptors (ERs) in the developing and adult human brain has not been clearly established, although estrogens are crucial for neuronal differentiation, synapse formation, and cognitive functions. By using immunohistochemistry, we have studied the distribution of ER alpha and ER beta in human cerebral cortex and hippocampus from early prenatal stages to adult life. ER alpha was detected in the cortex at 9 gestational weeks (GW), with a high expression in proliferating zones and the cortical plate.

Leptin receptors in human skeletal muscle.

Human skeletal muscle expresses leptin receptor mRNA; however, it remains unknown whether leptin receptors (OB-R) are also expressed at the protein level. Fourteen healthy men (age = 33.1 +/- 2.

Comparative aspects of p73 and Reelin expression in Cajal-Retzius cells and the cortical hem in lizard, mouse and human.

Cajal-Retzius (CR) cells of the mammalian neocortex co-express the extracellular matrix protein Reelin and p73, a transcription factor involved in cell death and survival. Most neocortical CR cells derive from the cortical hem, with minor additional sources. We analyzed the distribution of Reelin and p73 immunoreactive (ir) neurons in the telencephalon of Lacerta galloti from early embryonic stages to hatching.