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Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring(More)
PURPOSE OF REVIEW New research on the mechanisms of neurodegeneration highlights parallels between prion disease pathogenesis and other, more common disorders not typically thought to be infectious. This involves propagation of protein misfolding from cell to cell by templated conformational change. This review focuses on the cell biology that underlies(More)
Although tau is a cytoplasmic protein, it is also found in brain extracellular fluids, e.g., CSF. Recent findings suggest that aggregated tau can be transferred between cells and extracellular tau aggregates might mediate spread of tau pathology. Despite these data, details of whether tau is normally released into the brain interstitial fluid (ISF), its(More)
Tau amyloid assemblies propagate aggregation from the outside to the inside of a cell, which may mediate progression of the tauopathies. The critical size of Tau assemblies, or "seeds," responsible for this activity is currently unknown, but this could be important for the design of effective therapies. We studied recombinant Tau repeat domain (RD) and Tau(More)
Aggregation of the microtubule associated protein Tau is associated with several neurodegenerative disorders, including Alzheimer disease and frontotemporal dementia. In Alzheimer disease, Tau pathology spreads progressively throughout the brain, possibly along existing neural networks. However, it is still unclear how the propagation of Tau misfolding(More)
Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is(More)
Previously, a number of analgesic agonists, when administered i.c.v. to mice, were shown putatively to activate the release of dynorphin A (1-17) (Dyn A) in the spinal cord. Whether released endogenously or administered i.t., Dyn A produces an antianalgesic action against i.t. administered morphine. In the present study, the opioid antagonists, naloxone and(More)
Prions derived from the prion protein (PrP) were first characterized as infectious agents that transmit pathology between individuals. However, the majority of cases of neurodegeneration caused by PrP prions occur sporadically. Proteins that self-assemble as cross-beta sheet amyloids are a defining pathological feature of infectious prion disorders and all(More)
Morphine given intracerebroventricularly releases spinal dynorphin A (Dyn) in mice. The present study was undertaken to determine whether morphine given intrathecally (IT) released Dyn. We demonstrated that the antinociceptive action of morphine was enhanced by procedures that are known to attenuate Dyn action. First, coadministration of the opiate(More)
Cold water swim stress for 3 min at 5 degrees C produces antinociception in the tail-flick test in mice by activation of delta opioid receptors in the brain. Also, the inhibition of the tail-flick reflex produced by i.c.v. administration of delta opioid receptor agonists is known to be mediated by spinal gamma-aminobutyric acid (GABA) receptors. The purpose(More)