Breaking Down Glioma-Microenvironment Crosstalk.

High-grade gliomas (HGGs) are the commonest primary brain cancers. They are characterized by a pattern of aggressive growth and diffuse infiltration of the host brain that severely limits the efficacy of conventional treatments and patient outcomes, which remain generally poor. Recent work has described a suite of mechanisms via which HGGs interact, predominantly bidirectionally, with various cell types in the host brain including neurons, glial cells, immune cells, and vascular elements to drive tumor growth and invasion.

Amyloid-β in Alzheimer's disease - front and centre after all?

The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer's disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer's research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others.

Friend or Foe? The Varied Faces of Homeostatic Synaptic Plasticity in Neurodegenerative Disease.

Homeostatic synaptic plasticity (HSP) regulates synaptic strength both pre- and postsynaptically to ensure stability and efficient information transfer in neural networks. A number of neurological diseases have been associated with deficits in HSP, particularly diseases characterised by episodic network instability such as migraine and epilepsy. Recently, it has become apparent that HSP also plays a role in many neurodegenerative diseases.

Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau.

In Alzheimer's disease, soluble oligomers of the amyloid-β peptide (Aβ) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aβ-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD).

A Novel Optical Quantal Analysis of Miniature Events Reveals Enhanced Frequency Following Amyloid β Exposure.

Non-evoked miniature release of neurotransmitters is increasingly recognized as playing an important role in neural function and is implicated in synaptic plasticity, metaplasticity, and homeostasis. Spontaneous miniature release events (minis) are usually measured electrophysiologically by recording the miniature postsynaptic currents (mEPSCs) that they evoke. However, this indirect technique can be confounded by changes within the postsynaptic neuron.

Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms.

Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus.

Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca signaling.

Acidic organelles, such as endosomes and lysosomes, store Ca that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca store signaling in murine hippocampal neurons.

The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons.

Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically.

Cell-Specific Loss of SNAP25 from Cortical Projection Neurons Allows Normal Development but Causes Subsequent Neurodegeneration.

Synaptosomal associated protein 25 kDa (SNAP25) is an essential component of the SNARE complex regulating synaptic vesicle fusion. SNAP25 deficiency has been implicated in a variety of cognitive disorders. We ablated SNAP25 from selected neuronal populations by generating a transgenic mouse (B6-Snap25tm3mcw (Snap25-flox)) with LoxP sites flanking exon5a/5b.

Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca Channels at Mammalian Hippocampal Synapses.

Voltage-dependent Ca channels (VGCC) represent the principal source of Ca ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity.

Is Parkinson's disease truly a prion-like disorder? An appraisal of current evidence.

Parkinson's disease (PD) is the world's second most common neurodegenerative disease and most common movement disorder. Characterised by a loss of dopaminergic neurons and the development of intraneuronal inclusions known as Lewy bodies, it has classically been thought of as a cell-autonomous disease. However, in 2008, two groups reported the startling observation of Lewy bodies within embryonic neuronal grafts transplanted into PD patients little more than a decade previously, suggesting that PD pathology can be propagated to neighbouring cells and calling basic assumptions of our understanding of the disease into question.

Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus.

The effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-d-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood.

Cerebral primitive neuroectodermal tumor in an adult with a heterozygous MSH2 mutation.

Background: A 37-year-old woman presented with a supratentorial cerebral mass, which was diagnosed histologically as a primitive neuroectodermal tumor. She had been treated for rectal adenocarcinoma 7 years previously. A family history revealed a young-onset colorectal carcinoma in the patient's father.

Brain histology.

In this article we summarise nervous system histology in health and disease and acquaint the reader with developments in the staining techniques that are in current use, particularly immunostains. Although clinicians do not need to know the details of stain appearances, some familiarity with these aspects of neuropathology is invaluable in interpreting the reports they receive from the laboratory, as well as reminding them of the amazing beauty of the central nervous system's microscopic structure.

A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse.

The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25). The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic beta-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials.

A mutation in Af4 is predicted to cause cerebellar ataxia and cataracts in the robotic mouse.

The robotic mouse is an autosomal dominant mutant that arose from a large-scale chemical mutagenesis program. It has a jerky, ataxic gait and develops adult-onset Purkinje cell loss in the cerebellum in a striking region-specific pattern, as well as cataracts. Genetic and physical mapping of the disease locus led to the identification of a missense mutation in a highly conserved region of Af4, a putative transcription factor that has been previously implicated in leukemogenesis.

Identification of a new Pmp22 mouse mutant and trafficking analysis of a Pmp22 allelic series suggesting that protein aggregates may be protective in Pmp22-associated peripheral neuropathy.

We have identified and characterized a new peripheral myelin protein 22 (Pmp22) mouse mutant. The mutation results in a serine to threonine amino acid substitution at residue 72, which is a hot spot for mutation in human PMP22, leading to the peripheral neuropathy Dejerine-Sottas syndrome. We have previously described two other Pmp22 mutants, providing an allelic series for gene function analysis.