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Genetics and neuropathology strongly link α-synuclein aggregation and neurotoxicity to the pathogenesis of Parkinson’s disease and related α-synucleinopathies. Here we describe a new Drosophila model of α-synucleinopathy based on widespread expression of wild-type human α-synuclein, which shows robust neurodegeneration, early-onset locomotor deficits, and abundant α-synuclein aggregation. We use results...
Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses...
The complex morphology of axons presents a challenge in understanding axonal responses to injury and disease. By in vivo two-photon imaging of spinal dorsal column sensory axons, we systematically examined the effect of injury location relative to the main bifurcation point on axon degeneration and regeneration following highly localized laser injuries. Retrograde but not anterograde degeneration...
For each environment a rodent has explored, its hippocampus contains a map consisting of a unique subset of neurons, called place cells, that have spatially tuned spiking there, with the remaining neurons being essentially silent. Using whole-cell recording in freely moving rats exploring a novel maze, we observed differences in intrinsic cellular properties and input-based subthreshold membrane potential...
The specificity of connections made by inhibitory interneurons in the neocortex is not well understood. In this issue of Neuron, Fino and Yuste (2011) use an enhanced version of two-photon glutamate uncaging, which preserves inhibitory synaptic transmission, to demonstrate that somatostatin-positive interneurons form densely convergent connections onto pyramidal cells in layer 2/3 of mouse frontal...
A central hypothesis for the limited capacity for adult central nervous system (CNS) axons to regenerate is the presence of myelin-derived axon growth inhibitors, the role of which, however, remains poorly understood. We have conducted a comprehensive genetic analysis of the three major myelin inhibitors, Nogo, MAG, and OMgp, in injury-induced axonal growth, including compensatory sprouting of uninjured...
The protein α-synuclein accumulates in the brain of patients with sporadic Parkinson's disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration. α-Synuclein localizes to the nerve terminal, but the knockout has little if any effect on synaptic transmission. In contrast, we now find that the...
Intracellular recording, which allows direct measurement of the membrane potential and currents of individual neurons, requires a very mechanically stable preparation and has thus been limited to in vitro and head-immobilized in vivo experiments. This restriction constitutes a major obstacle for linking cellular and synaptic physiology with animal behavior. To overcome this limitation we have developed...
Rats repeatedly ran through a sequence of spatial receptive fields of hippocampal CA1 place cells in a fixed temporal order. A novel combinatorial decoding method reveals that these neurons repeatedly fired in precisely this order in long sequences involving four or more cells during slow wave sleep (SWS) immediately following, but not preceding, the experience. The SWS sequences occurred intermittently...
Parkinson's disease (PD) is a common neurodegenerative disorder with no known cure. The etiology of PD is likely due, in part, to combinations of genetic susceptibilities and environmental factors. In rare familial cases, PD is due to genetic mutations. A number of new genetic and toxin models of PD and advances in older models are yielding important new information about the pathogenesis of PD. This...
Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired...
Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, FAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Aβ1–42 peptides...
Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1–42(43)/Aβ1–40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ1–42(43)/Aβ1–40...
The majority of early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genesPS1 and PS2, located on chromosome 14 and 1, respectively. Using two highly specific antibodies against nonoverlapping epitopes of the PS1- encoded polypeptide, termed presenilin 1 (PS1), we document that the preponderant PS1-related species that accumulate in cultured mammalian cells,...
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