Pathogenic Aβ production by heterozygous PSEN1 mutations is intrinsic to the mutant protein and not mediated by conformational hindrance of wild-type PSEN1.

Presenilin-1 (PSEN1) is the catalytic subunit of the intramembrane protease γ-secretase and undergoes endoproteolysis during its maturation. Heterozygous mutations in the PSEN1 gene cause early-onset familial Alzheimer's disease (eFAD) and increase the proportion of longer aggregation-prone amyloid-β peptides (Aβ42 and/or Aβ43). Previous studies had suggested that PSEN1 mutants might act in a dominant-negative fashion by functional impediment of wild-type PSEN1, but the exact mechanism by which PSEN1 mutants promote pathogenic Aβ production remains controversial.

Astrocyte lineage cells are essential for functional neuronal differentiation and synapse maturation in human iPSC-derived neural networks.

Human astrocytes differ dramatically in cell morphology and gene expression from murine astrocytes. The latter are well known to be of major importance in the formation of neuronal networks by promoting synapse maturation. However, whether human astrocyte lineage cells have a similar role in network formation has not been firmly established.

Contribution of astrocytes to metabolic dysfunction in the Alzheimer's disease brain.

Historically considered as accessory cells to neurons, there is an increasing interest in the role of astrocytes in normal and pathological conditions. Astrocytes are involved in neurotransmitter recycling, antioxidant supply, ion buffering and neuroinflammation, i.e.

Episomal plasmid-based generation of an iPSC line from a 79-year-old individual carrying the APOE4/4 genotype: i11001.

In this study, lymphoblastoid cells derived from a 79-year old individual with a history of progressive presenile dementia, were used to generate iPS cells, employing episomal plasmids expressing OCT4, SOX2, KLF4, LIN28, L-MYC and a p53 shRNA. The individual was homozygous for the APOE4 allele. The resulting iPS cells had a normal karyotype, retained the APOE4/4 genotype, expressed pluripotency markers, were free of genomically integrated plasmids, and could be differentiated into cell type representatives from the three germ layers in vitro.

Episomal plasmid-based generation of an iPSC line from an 83-year-old individual carrying the APOE4/4 genotype: i10984.

In this study, lymphoblastoid cells derived from a 83-year old individual with a 15year history of progressive presenile dementia, were used to generate iPS cells, employing episomal plasmids expressing OCT4, SOX2, LIN28, L-MYC and a p53 shRNA. The individual was homozygous for the APOE4 allele. The resulting iPS cells had a normal karyotype, retained the APOE4/4 genotype, expressed pluripotency markers, were free of genomically integrated plasmids, and could be differentiated into cell type representatives from the three germ layers in vitro.

mESC-based in vitro differentiation models to study vascular response and functionality following genotoxic insults.

Because of high exposure to systemic noxae, vascular endothelial cells (EC) have to ensure distinct damage defense and regenerative mechanisms to guarantee vascular health. For meaningful toxicological drug assessments employing embryonic stem cell (ESC)-based in vitro models, functional competence of differentiated progeny and detailed knowledge regarding damage defense mechanisms are essential. Here, mouse ESCs (mESC) were differentiated into functionally competent vascular cells (EC and smooth muscle cells [SMC]).

Embryonic stem cells stably expressing BDNF-GFP exhibit a BDNF-release-dependent enhancement of neuronal differentiation.

Brain-derived neurotrophic factor (BDNF) is known to be a crucial regulator of neuronal survival and synaptic plasticity in the mammalian brain. Furthermore, BDNF positively influences differentiation of embryonic neural precursors, as well as that of neural stem cells from adult neurogenic niches. To study the impact of cell-released BDNF on neural differentiation of embryonic stem cells (ESCs), which represent an attractive source for cell transplantation studies, we have generated mouse ESC clones overexpressing BDNF-GFP by use of knock-in technology.

Asymmetric N-cadherin expression results in synapse dysfunction, synapse elimination, and axon retraction in cultured mouse neurons.

Synapse elimination and pruning of axon collaterals are crucial developmental events in the refinement of neuronal circuits. While a control of synapse formation by adhesion molecules is well established, the involvement of adhesion molecules in developmental synapse loss is poorly characterized. To investigate the consequences of mis-match expression of a homophilic synaptic adhesion molecule, we analysed an asymmetric, exclusively postsynaptic expression of N-cadherin.

C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β.

The aetiology of Alzheimer's disease is thought to include functional impairment of synapses and synapse loss as crucial pathological events leading to cognitive dysfunction and memory loss. Oligomeric amyloid-β peptides are well known to induce functional damage, destabilization and loss of brain synapses. However, the complex molecular mechanisms of amyloid-β action resulting ultimately in synapse elimination are incompletely understood, thus limiting knowledge of potential therapeutic targets.

Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats.

Neurons have a high demand for cholesterol to develop and maintain membrane-rich structures like axons, dendrites and synapses, but it remains unclear, whether they can satisfy their need by costly de novo synthesis. To address this, we compared cholesterol synthesis in serum-free cultures of highly purified CNS neurons and glial cells from postnatal rats. We observed marked cell-specific differences: Compared with glial cells, neurons showed different profiles of biosynthetic enzymes, post-squalene precursors and cholesterol metabolites, and they produced cholesterol less efficiently, possibly because of very low levels of lanosterol-converting enzymes.

Glia-induced neuronal differentiation by transcriptional regulation.

There is increasing evidence that different phases of brain development depend on neuron-glia interactions including postnatal key events like synaptogenesis. To address how glial cells influence synapse development, we analyzed whether and how glia-derived factors affect gene expression in primary cultures of immunoisolated rat retinal ganglion cells (RGCs) by oligonucleotide microarrays. Our results show that the transcript pattern matched the developmental stage and characteristic properties of RGCs in vitro.