Total cell N-glycosylation is altered during differentiation of induced pluripotent stem cells to neural stem cells and is disturbed by trisomy 21.

Down syndrome (DS), a genetic condition caused by trisomy 21 (T21), manifests various neurological symptoms, including intellectual disability, early neurodegeneration, and early-onset dementia. N-glycosylation is a protein modification that plays a critical role in numerous neurobiological processes and whose dysregulation is associated with a range of neurological disorders. However, whether N-glycosylation of neural glycoproteins is affected in DS has not been studied.

Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.

GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits.

Cerebral organoids with chromosome 21 trisomy secrete Alzheimer's disease-related soluble aggregates detectable by single-molecule-fluorescence and super-resolution microscopy.

Understanding the role of small, soluble aggregates of beta-amyloid (Aβ) and tau in Alzheimer's disease (AD) is of great importance for the rational design of preventative therapies. Here we report a set of methods for the detection, quantification, and characterisation of soluble aggregates in conditioned media of cerebral organoids derived from human iPSCs with trisomy 21, thus containing an extra copy of the amyloid precursor protein (APP) gene. We detected soluble beta-amyloid (Aβ) and tau aggregates secreted by cerebral organoids from both control and the isogenic trisomy 21 (T21) genotype.

BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2).

Mechanical Stress Induces a Transient Suppression of Cytokine Secretion in Astrocytes Assessed at the Single-Cell Level with a High-Throughput Microfluidic Chip.

Brain cells are constantly subjected to mechanical signals. Astrocytes are the most abundant glial cells of the central nervous system (CNS), which display immunoreactivity and have been suggested as an emerging disease focus in the recent years. However, how mechanical signals regulate astrocyte immunoreactivity, and the cytokine release in particular, remains to be fully characterized.

RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia.

Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices.

Localized delivery of CRISPR/dCas9 via layer-by-layer self-assembling peptide coating on nanofibers for neural tissue engineering.

The clustered regularly interspaced short palindromic repeat (CRISPR) systems have a wide variety of applications besides precise genome editing. In particular, the CRISPR/dCas9 system can be used to control specific gene expression by CRISPR activation (CRISPRa) or interference (CRISPRi). However, the safety concerns associated with viral vectors and the possible off-target issues of systemic administration remain huge concerns to be safe delivery methods for CRISPR/Cas9 systems.

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.

Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome.

Enlarged early endosomes have been visualized in Alzheimer's disease (AD) and Down syndrome (DS) using conventional confocal microscopy at a resolution corresponding to endosomal size (hundreds of nm). In order to overtake the diffraction limit, we used super-resolution structured illumination microscopy (SR-SIM) and transmission electron microscopies (TEM) to analyze the early endosomal compartment in DS.By immunofluorescence and confocal microscopy, we confirmed that the volume of Early Endosome Antigen 1 (EEA1)-positive puncta was 13-19% larger in fibroblasts and iPSC-derived neurons from individuals with DS, and in basal forebrain cholinergic neurons (BFCN) of the Ts65Dn mice modelling DS.

Differential Coassembly of α1-GABARs Associated with Epileptic Encephalopathy.

GABA receptors (GABARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren syndrome identified a frameshifting variant in a major GABAR gene, This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1* Cell surface expression of mutant murine GABARs is severely impaired compared with WT, due to retention in the endoplasmic reticulum.

Modeling Down syndrome in cells: From stem cells to organoids.

Down Syndrome (DS) is a complex chromosomal disorder, with neurological issues, featuring among the symptoms. Primary neuronal cells and tissues are extremely useful, but limited both in supply and experimental manipulability. To better understand the cellular, molecular and pathological mechanisms involved in DS neurodevelopment and neurodegeneration, a range of different cellular models have been developed over the years including human: mouse hybrid cells, transchromosomic mouse embryonic stem cells (ESCs) and human ESC and induced pluripotent stem cells derived from different sources.

Effects of miR-219/miR-338 on microglia and astrocyte behaviors and astrocyte-oligodendrocyte precursor cell interactions.

MiR-219 and miR-338 (miR-219/miR-338) are oligodendrocyte-specific microRNAs. The overexpression of these miRs in oligodendrocyte precursor cells promotes their differentiation and maturation into oligodendrocytes, which may enhance axonal remyelination after nerve injuries in the central nervous system (CNS). As such, the delivery of miR-219/miR-338 to the CNS to promote oligodendrocyte precursor cell differentiation, maturation and myelination could be a promising approach for nerve repair.

Correction: Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells.

Correction for 'Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells' by Wai Hon Chooi et al., Biomater. Sci.

Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years.

Importance: This work quantifies the fatal burden of dementia associated with Alzheimer disease in individuals with Down syndrome (DS).

Objective: To explore the association of dementia associated with Alzheimer disease with mortality and examine factors associated with dementia in adults with DS.

Design, Settings And Participants: Prospective longitudinal study in a community setting in England.

Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells.

The use of human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) is an attractive therapeutic option for damaged nerve tissues. To direct neuronal differentiation of stem cells, we have previously developed an electrospun polycaprolactone nanofiber scaffold that was functionalized with siRNA targeting Re-1 silencing transcription factor (REST), by mussel-inspired bioadhesive coating. However, the efficacy of nanofiber-mediated RNA interference on hiPSC-NPCs differentiation remains unknown.

LEE011 and ruxolitinib: a synergistic drug combination for natural killer/T-cell lymphoma (NKTCL).

Natural killer/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma that has been facing limited success with conventional treatments, urging for the discovery of alternative strategies. Recent studies including ours have revealed that EZH2 and JAK-STAT signalling pathways are key contributors to NKTCL pathogenesis. In particular, we found that EZH2 is overexpressed and directly transcriptionally activates the gene to confer growth advantage.

Translating molecular advances in Down syndrome and Fragile X syndrome into therapies.

Ongoing treatments for genetic developmental disorders of the central nervous system are mostly symptomatic and do not correct the genetic cause. Recent identification of common mechanisms between diseases has suggested that new therapeutic targets could be applied across intellectual disabilities with potential disease-modifying properties. The European Down syndrome and other genetic developmental disorders (DSG2D) network joined basic and clinical scientists to foster this research and carry out clinical trials.

Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome.

Background: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions.

Methods: We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis.

Intracerebral haemorrhage in Down syndrome: protected or predisposed?

Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onset Alzheimer's disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition.

The importance of understanding individual differences in Down syndrome.

In this article, we first present a summary of the general assumptions about Down syndrome (DS) still to be found in the literature. We go on to show how new research has modified these assumptions, pointing to a wide range of individual differences at every level of description. We argue that, in the context of significant increases in DS life expectancy, a focus on individual differences in trisomy 21 at all levels-genetic, cellular, neural, cognitive, behavioral, and environmental-constitutes one of the best approaches for understanding genotype/phenotype relations in DS and for exploring risk and protective factors for Alzheimer's disease in this high-risk population.

Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP.

People with Down syndrome (DS) virtually all develop intellectual disability (ID) of varying degree of severity, and also have a high risk of early Alzheimer's disease (AD). ID prior to the onset of dementia, and its relationship to the onset of dementia in DS is a complex phenomenon influenced by many factors, and scarcely understood. Unraveling the causative factors and modulators of these processes remains a challenge, with potential to be informative for both ID and AD, for the development of early biomarkers and/or therapeutic approaches.

Behavioural and psychological symptoms of dementia in Down syndrome: Early indicators of clinical Alzheimer's disease?

Behavioural and Psychological Symptoms of Dementia (BPSD) are a core symptom of dementia and are associated with suffering, earlier institutionalization and accelerated cognitive decline for patients and increased caregiver burden. Despite the extremely high risk for Down syndrome (DS) individuals to develop dementia due to Alzheimer's disease (AD), BPSD have not been comprehensively assessed in the DS population. Due to the great variety of DS cohorts, diagnostic methodologies, sub-optimal scales, covariates and outcome measures, it is questionable whether BPSD have always been accurately assessed.