Resilience to Alzheimer's disease associates with alterations in perineuronal nets.

Introduction: Some individuals show intact cognition despite the presence of neuropathological hallmarks of Alzheimer's disease (AD). The plasticity of parvalbumin (PV)-containing interneurons might contribute to resilience. Perineuronal nets (PNNs), that is, extracellular matrix structures around neurons, modulate PV neuron function.

Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies.

Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.

Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1 mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons.

Production of High-Yield Adeno Associated Vector Batches Using HEK293 Suspension Cells.

Adeno-associated viral vectors (AAVs) are a remarkable tool for investigating the central nervous system (CNS). Innovative capsids, such as AAV.PHP.

Gene-expression profiling of individuals resilient to Alzheimer's disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response.

Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer's disease (AD). This phenomenon has been referred to as 'resilience'. The molecular and cellular underpinnings of resilience remain poorly understood.

The concept of resilience to Alzheimer's Disease: current definitions and cellular and molecular mechanisms.

Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer's Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood.

Improving adeno-associated viral (AAV) vector-mediated transgene expression in retinal ganglion cells: comparison of five promoters.

Recombinant adeno-associated viral vectors (AAVs) are an effective system for gene transfer. AAV serotype 2 (AAV2) is commonly used to deliver transgenes to retinal ganglion cells (RGCs) via intravitreal injection. The AAV serotype however is not the only factor contributing to the effectiveness of gene therapies.

Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline.

Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell signaling both before and after sciatic nerve injury (SNI) in mice.

Molecular Changes in the Dorsal Root Ganglion during the Late Phase of Peripheral Nerve Injury-induced Pain in Rodents: A Systematic Review.

The dorsal root ganglion is widely recognized as a potential target to treat chronic pain. A fundamental understanding of quantitative molecular and genomic changes during the late phase of pain is therefore indispensable. The authors performed a systematic literature review on injury-induced pain in rodent dorsal root ganglions at minimally 3 weeks after injury.

The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity.

The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking.

Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing.

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice.

The Effect of Inflammatory Priming on the Therapeutic Potential of Mesenchymal Stromal Cells for Spinal Cord Repair.

Mesenchymal stromal cells (MSC) are used for cell therapy for spinal cord injury (SCI) because of their ability to support tissue repair by paracrine signaling. Preclinical and clinical research testing MSC transplants for SCI have revealed limited success, which warrants the exploration of strategies to improve their therapeutic efficacy. MSC are sensitive to the microenvironment and their secretome can be altered in vitro by exposure to different culture media.

Semaphorins in Adult Nervous System Plasticity and Disease.

Semaphorins, originally discovered as guidance cues for developing axons, are involved in many processes that shape the nervous system during development, from neuronal proliferation and migration to neuritogenesis and synapse formation. Interestingly, the expression of many Semaphorins persists after development. For instance, Semaphorin 3A is a component of perineuronal nets, the extracellular matrix structures enwrapping certain types of neurons in the adult CNS, which contribute to the closure of the critical period for plasticity.

Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury.

A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery.

An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity.

During restricted time windows of postnatal life, called critical periods, neural circuits are highly plastic and are shaped by environmental stimuli. In several mammalian brain areas, from the cerebral cortex to the hippocampus and amygdala, the closure of the critical period is dependent on the formation of perineuronal nets. Perineuronal nets are a condensed form of an extracellular matrix, which surrounds the soma and proximal dendrites of subsets of neurons, enwrapping synaptic terminals.

CERT reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease.

Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains.

Macrophage-Derived Inflammation Induces a Transcriptome Makeover in Mesenchymal Stromal Cells Enhancing Their Potential for Tissue Repair.

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome.

GDNF Gene Therapy to Repair the Injured Peripheral Nerve.

A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process.

Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries.

Schwann cell grafts support axonal growth following spinal cord injury, but a boundary forms between the implanted cells and host astrocytes. Axons are reluctant to exit the graft tissue in large part due to the surrounding inhibitory environment containing chondroitin sulphate proteoglycans (CSPGs). We use a lentiviral chondroitinase ABC, capable of being secreted from mammalian cells (mChABC), to examine the repercussions of CSPG digestion upon Schwann cell behaviour in vitro.

Optimization of adeno-associated viral vector-mediated transduction of the corticospinal tract: comparison of four promoters.

Adeno-associated viral vectors are widely used as vehicles for gene transfer to the nervous system. The promoter and viral vector serotype are two key factors that determine the expression dynamics of the transgene. A previous comparative study has demonstrated that AAV1 displays efficient transduction of layer V corticospinal neurons, but the optimal promoter for transgene expression in corticospinal neurons has not been determined yet.

Combining timed GDNF and ChABC gene therapy to promote long-distance regeneration following ventral root avulsion and repair.

Ventral root avulsion leads to severe motoneuron degeneration and prolonged distal nerve denervation. After a critical period, a state of chronic denervation develops as repair Schwann cells lose their pro-regenerative properties and inhibitory factors such as CSPGs accumulate in the denervated nerve. In rats with ventral root avulsion injuries, we combined timed GDNF gene therapy delivered to the proximal nerve roots with the digestion of inhibitory CSPGs in the distal denervated nerve using sustained lentiviral-mediated chondroitinase ABC (ChABC) enzyme expression.

Regeneration of adult rat sensory and motor neuron axons through chimeric peroneal nerve grafts containing donor Schwann cells engineered to express different neurotrophic factors.

Large peripheral nerve (PN) defects require bridging substrates to restore tissue continuity and permit the regrowth of sensory and motor axons. We previously showed that cell-free PN segments repopulated ex vivo with Schwann cells (SCs) transduced with lentiviral vectors (LV) to express different growth factors (BDNF, CNTF or NT-3) supported the regeneration of axons across a 1 cm peroneal nerve defect (Godinho et al., 2013).

ORANGE: A CRISPR/Cas9-based genome editing toolbox for epitope tagging of endogenous proteins in neurons.

The correct subcellular distribution of proteins establishes the complex morphology and function of neurons. Fluorescence microscopy techniques are invaluable to investigate subcellular protein distribution, but they suffer from the limited ability to efficiently and reliably label endogenous proteins with fluorescent probes. We developed ORANGE: Open Resource for the Application of Neuronal Genome Editing, which mediates targeted genomic integration of epitope tags in rodent dissociated neuronal culture, in organotypic slices, and in vivo.