The 31,000-plus scientists who descended on the U.S. capital for the Society for Neuroscience annual meeting, November 15-19, made for an enthusiastic crowd, even though there were fewer Alzheimer’s sessions than in previous years. From nifty new tools (read: Aβ electrode) to potential paradigm shifts (read: provenance of plaque microglia), Alzforum reporters will bring you highlights over the coming weeks. One announcement at the meeting was that Michela Gallagher of Johns Hopkins University, Baltimore, won the 2014 Mika Salpeter Lifetime Achievement Award. The society bestows this honor on leaders who have also promoted the advancement of female neuroscientists. Gallagher studies the effect of aging on cognition and, among other findings, discovered that overactivation of the hippocampus may cause people to forget, rather than remember (see May 2012 research news).
Perhaps the biggest surprise at this year's meeting, a "game changer" to some scientists, came from studies of TREM2. This glial receptor made a splash two years ago when geneticists reported that a variant increased the risk for AD by around threefold. At SfN, researchers claimed that TREM2-positive cells that hover around plaques in the brain are not brain-resident microglia at all, but are in fact peripheral monocytes. If confirmed, this would represent a departure from what many in the field have assumed—namely that the glia mopping up Aβ plaques are brain-derived.
In related glial news, GE180, a PET ligand for tracking microglial activation, made its mark. Like other glial tracers that have been developed, GE180 binds a mitochondrial transporter protein called TSPO. Unlike the prototype TSPO ligand PK11195, however, GE180's PET signal comes from fluorine-18, which is more suitable for imaging, given its longer half-life. As a microglial tracer, GE180 appears to be more specific and selective than its predecessors, and researchers at the meeting were excited by the possibility of finally having a glial tracer that might work well in people. The tracer has been tested preclinically. Researchers reported that in a mouse model of AD, an experimental therapeutic returned GE180 uptake in the brain to baseline levels within three months.
In another technological advance, scientists at Washington University, St. Louis, have developed an Aβ electrode (see image below) that can measure changes in the concentration of the peptide in the brain over a 30-second time span, allowing researchers to more accurately track Aβ dynamics. The technology uses an Aβ antibody-tipped electrode. It could be adapted to measure other proteins, including tau, and potentially different forms of Aβ, though for now it appears to detect only monomers. Researchers at the meeting were intrigued at the possible uses for such electrodes. In other Aβ developments, researchers from CogRx, a small company in Pittsburgh, reported new compounds that attenuate the peptide's toxicity. They displace various forms of Aβ, including oligomers isolated from patient brains, from the cell surface, and CogRx has identified sigma-2/progesterone receptor membrane component 1 as a specific binding receptor for the compounds. The company plans to enter compounds into human trials early next year. In the "out of left field" category, scientists from Revalesio, a small company in Tacoma, Washington, reported that "nanobubbles," positively charged spheres laden with oxygen, improve pathology and behavior in the 5xFAD mouse model of AD. Before eyes roll, dear reader, get the full story to judge for yourself whether the science behind these anti-inflammatory bubbles seems solid. They are in clinical testing for a variety of conditions.
More unusual receptors made the news at SfN. Researchers reported that the P2Y1 subtype of ATP purinergic receptor in astrocytes promotes hyperactivation of these cells around plaques, a phenomenon that has been observed for decades. While P2YI turns on early in AD, perhaps even before plaques appear, an inhibitor of the receptor restored normal astrocytic activity in transgenic APP mice. Another purinergic receptor, the A2A adenosine receptor, has also been implicated in the disease. At SfN, researchers reported that in people with AD, and in transgenic mouse models, astrocytes overexpressed this receptor. A2A levels correlated with plaque burden and disease progression. Genetically removing these receptors from astrocytes in APP transgenic mice improved their memory, while activating them did the opposite. The findings suggest that the A2A purine receptor in astrocytes contributes to memory loss in AD.
Calcium dysregulation may be another early casualty of the disease. Researchers know that expression of endoplasmic reticulum ryanodine channels, and calcium signaling through these channels, goes up in AD-transgenic mice before they develop memory deficits. New data at SfN suggested that preventing this calcium dyshomeostasis preserves hippocampal synapses and spines, and restores synaptic plasticity. This made researchers think that targeting the ryanodine receptor might be worth trying in AD patients. Compounds that restore calcium homeostasis and RyR-signaling in hippocampal slice preparations and in AD mice in vivo are prototypes for potential drug discovery.
There was plenty of basic biology on display at SfN as well. Exosomes were a hot topic in a special lecture and mini- and nanosymposia, including one co-chaired by Xandra Breakefield from Massachusetts General Hospital, Boston, who won the 2013 Mika Salpeter Award. Scientists reported new ways in which these small extracellular vesicles function in cell-to-cell communication in the nervous system. New evidence suggests that cells specially prepare and package protein and RNA into exosomes to be delivered to other cells, where they affect axon growth and cell survival. Brain tumor cells may use them to prime the environment for their growth. Exosomes may also conspire in the spread of proteins involved in neurodegenerative disease. Evidence from stem cells suggests that neuronal exosomes spread Aβ and α-synuclein, while another study implicated microglial exosomes in the spread of tau. In addition, studies hinted that amyloid precursor protein and the secretases necessary for Aβ production can be enveloped in exosomes, hinting that the peptide might be produced in these vesicles outside the cell. Neurons from Down’s syndrome patients expel more exosomes than do control neurons, which may partly explain why these people accumulate so much Aβ in their brain. Scientists at the meeting wondered if these mechanisms could offer new targets for preventing the spread of pathogenic proteins around the central nervous system.
In genetics news, researchers at Genentech reported a rare coding mutation that associates with AD in two families affected by late-onset disease. They corroborated the finding in four case/control cohorts. The mutation lies in the UNC5C gene; it encodes a Netrin receptor that directs axon migration during development. Since the mutation doubles risk for AD, making it one of the strongest risk factors after ApoE4 and TREM2, researchers at the conference hailed the finding as potentially important. In vitro data suggests this mutation increases susceptibility to Aβ toxicity, causing cell death.
In other genetics reports, researchers claimed that a mutation in Tmp21, a modulator of γ-secretase cleavage, associates with AD, while calling a mutation that decreases expression of CD33 protective. In the search for such protective variants, many groups have looked to older people with ApoE4 who seem to defy their odds and live free of dementia past age 75. At SfN, researchers reported finding protective variants in genes previously associated with AD in a cohort of 24 people who are homozygous for ApoE4. They also spotted potentially protective mutations in genes involved in pathways that have been implicated in the disease.—Tom Fagan and Gwyneth Zakaib
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