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Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Alzheimer's disease: The forgetting gene

Alzheimer's disease: The forgetting gene | Neuroscience_topics | Scoop.it

For decades, most researchers ignored the leading genetic risk factor for Alzheimer's disease. That is set to change. 

One day in 1991, neurologist Warren Strittmatter asked his boss to look at some bewildering data. Strittmatter was studying amyloid-β, the main component of the molecular clumps found in the brains of people with Alzheimer's disease. He was hunting for amyloid-binding proteins in the fluid that buffers the brain and spinal cord, and had fished out one called apolipoprotein E (ApoE), which had no obvious connection with the disease. (...) - by Laura Spinney, Nature, 04 June 2014

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Major Discovery For Alzheimer\'s Disease

Major Discovery For Alzheimer\'s Disease | Neuroscience_topics | Scoop.it

The Journal of Neuroscience has published a study led by researchers at the Max Planck Florida Institute for Neuroscience, the first and only U.S. extension of the prestigious Max Planck Society, that may hold a stunning breakthrough in the fight to treat Alzheimer's disease. The study potentially identifies a cause of Alzheimer's disease - based on a newly-discovered signaling pathway in cellular models of Alzheimer's disease - and opens the door for new treatments by successfully blocking this pathway. The Institute, which recently opened in December 2012, focuses solely on basic neuroscience research that aims to analyze, map, and decode the human brain - the most important and least understood organ in the body.(...)

The MPFI research indicates that the presence of Amyloid beta triggers increased levels of a signaling protein, called centaurin-alpha1 (CentA1), that appears to cause neuronal dysfunction - a potentially groundbreaking discovery that uncovers an important intermediary step in the progression of the disease. 
As part of the research, the scientists were able to identify CentA1 and measure its negative effects on neurons. Utilizing an RNA silencing technique, they turned down the cellular production of CentA1, and showed that affected neurons, exposed to Amyloid beta and exhibiting Alzheimer's related symptoms, returned to normal morphology and synaptic function, even with the continued presence of Amyloid beta. They further found that increased CentA1 activates a series of proteins, and these proteins form a signaling pathway from CentA1 to neuronal dysfunction. Thus, inhibiting other proteins in the pathway also "cured" affected neurons. (...) - Medical News Today, 21 March, 2013

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Major step toward an Alzheimer's vaccine

A team of researchers from Université Laval, CHU de Québec, and pharmaceutical firm GlaxoSmithKline (GSK) has discovered a way to stimulate the brain's natural defense mechanisms in people with Alzheimer's disease. This major breakthrough, details of which are presented today in an early online edition of the Proceedings of the National Academy of Sciences (PNAS), opens the door to the development of a treatment for Alzheimer's disease and a vaccine to prevent the illness. (...) - eurekalert, 15/02/2013

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Brain excitability and connectivity of neuronal assemblies in Alzheimer's disease: From animal models to human findings

Brain excitability and connectivity of neuronal assemblies in Alzheimer's disease: From animal models to human findings | Neuroscience_topics | Scoop.it

[Review] The human brain contains about 100 billion neurons forming an intricate network of innumerable connections, which continuously adapt and rewire themselves following inputs from external and internal environments as well as the physiological synaptic, dendritic and axonal sculpture during brain maturation and throughout the life span.

Growing evidence supports the idea that Alzheimer's disease (AD) targets selected and functionally connected neuronal networks and, specifically, their synaptic terminals, affecting brain connectivity well before producing neuronal loss and compartmental atrophy.

The understanding of the molecular mechanisms underlying the dismantling of neuronal circuits and the implementation of ‘clinically oriented’ methods to map-out the dynamic interactions amongst neuronal assemblies will enhance early/pre-symptomatic diagnosis and monitoring of disease progression. More important, this will open the avenues to innovative treatments, bridging the gap between molecular mechanisms and the variety of symptoms forming disease phenotype.

In the present review a set of evidence supports the idea that altered brain connectivity, exhausted neural plasticity and aberrant neuronal activity are facets of the same coin linked to age-related neurodegenerative dementia of Alzheimer type.

Investigating their respective roles in AD pathophysiology will help in translating findings from basic research to clinical applications. (...) - By D'Amelio M & Rossini PMProgress in Neurobiology, Volume 99, Issue 1, October 2012, Pages 42–60

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Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons

Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons | Neuroscience_topics | Scoop.it

Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrPC) selectively binds oligomeric Aβ and can mediate Alzheimer's disease–related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrPC complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrPC is enriched in postsynaptic densities, and Aβ-PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrPC to activate Fyn. Aβ engagement of PrPC-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrPC and Fyn, and human familial Alzheimer's disease transgene–induced convulsive seizures did not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway that requires PrPC and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease. - Um JW et al.Nature Neuroscience 15, 1227–1235, 22 July 2012

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Biomarkers could predict Alzheimer's before it starts

Biomarkers could predict Alzheimer's before it starts | Neuroscience_topics | Scoop.it

Study identifies potential blood test for cognitive decline.

A simple blood test has the potential to predict whether a healthy person will develop symptoms of dementia within two or three years. If larger studies uphold the results, the test could fill a major gap in strategies to combat brain degeneration, which is thought to show symptoms only at a stage when it too late to treat effectively. (...) - by Alison Abbott, Nature, 09 March 2014

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Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression

The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer’s disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer’s disease. (...) - by Kessels HW et al.PNASMarch 5, 2013 vol. 110 no. 104033-4038

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The alterations of Ca2+/calmodulin/CaMKII/CaV1.2 signaling in experimental models of Alzheimer's disease and vascular dementia

The alterations of Ca2+/calmodulin/CaMKII/CaV1.2 signaling in experimental models of Alzheimer's disease and vascular dementia | Neuroscience_topics | Scoop.it
Highlights
  • CaM was up-regulated in the hippocampus of both APP/PS1 mice and VD gerbils.
  • The expression of CaV1.2 protein was increased in VD gerbils and in cultured neurons but decreased in APP/PS1 mice.
  • The number of CaMKII and CaV1.2 co-localization positive neurons was decreased in AD and VD models.

    (...) - by Min D et al., Neuroscience LettersIn Press, Corrected Proof, Available online 8 February 2013
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Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology

Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer’s disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ42 normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system may be functional and biochemical indicators, respectively, of Aβ-associated pathology. - by Roh JH et al.Sci Transl Med 5 September 2012: Vol. 4, Issue 150, p. 150ra122

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