Control of cell surface expression of GABAA receptors by a conserved region at the end of the N-terminal extracellular domain of receptor subunits.

Type A γ-aminobutyric acid receptors (GABAARs) represent a family of pentameric GABA-gated Cl-/HCO3- ion channels which mediate inhibitory transmission in the central nervous system. Cell surface expression of GABAARs, a prerequisite for their function, is dependent on the appropriate assembly of the receptor subunits and their transient interactions with molecular chaperones within the endoplasmic reticulum (ER) and Golgi apparatus. Here, we describe a highly conserved amino acid sequence within the extracellular N-terminal domain of the receptor subunits adjoining the first transmembrane domain as a region important for GABAAR processing within the ER. Modifications of this region in the α1, ß3, and γ2 subunits using insertion or site-directed mutagenesis impaired GABAAR trafficking to the cell surface in heterologous cell systems although they had no effect on the subunit assembly. We found that mutated receptors accumulated in the ER where they were shown to associate with chaperones calnexin, BiP, and Grp94. However, their surface expression was increased when ER-associated degradation or proteosome function was inhibited, while modulation of ER calcium stores had little effect. When compared to the wt, mutated receptors showed decreased interaction with calnexin, similar binding to BiP, and increased association with Grp94. Structural modeling of calnexin interaction with the wt or mutated GABAAR revealed that disruption in structure caused by mutations in the conserved region adjoining the first transmembrane domain may impair calnexin binding. Thus, this previously uncharacterized region plays an important role in intracellular processing of GABAARs at least in part by stabilizing their interaction with calnexin.

Proper-motion age dating of the progeny of Nova Scorpii AD 1437.

'Cataclysmic variables' are binary star systems in which one star of the pair is a white dwarf, and which often generate bright and energetic stellar outbursts. Classical novae are one type of outburst: when the white dwarf accretes enough matter from its companion, the resulting hydrogen-rich atmospheric envelope can host a runaway thermonuclear reaction that generates a rapid brightening. Achieving peak luminosities of up to one million times that of the Sun, all classical novae are recurrent, on timescales of months to millennia. During the century before and after an eruption, the 'novalike' binary systems that give rise to classical novae exhibit high rates of mass transfer to their white dwarfs. Another type of outburst is the dwarf nova: these occur in binaries that have stellar masses and periods indistinguishable from those of novalikes but much lower mass-transfer rates, when accretion-disk instabilities drop matter onto the white dwarfs. The co-existence at the same orbital period of novalike binaries and dwarf novae-which are identical but for their widely varying accretion rates-has been a longstanding puzzle. Here we report the recovery of the binary star underlying the classical nova eruption of 11 March AD 1437 (refs 12, 13), and independently confirm its age by proper-motion dating. We show that, almost 500 years after a classical-nova event, the system exhibited dwarf-nova eruptions. The three other oldest recovered classical novae display nova shells, but lack firm post-eruption ages, and are also dwarf novae at present. We conclude that many old novae become dwarf novae for part of the millennia between successive nova eruptions.

Informing the management of multiple stressors on estuarine ecosystems using an expert-based Bayesian Network model.

The approach of applying stressor load limits or thresholds to aid estuarine management is being explored in many global case studies. However, there is growing concern regarding the influence of multiple stressors and their cumulative effects on the functioning of estuarine ecosystems due to the considerable uncertainty around stressor interactions. Recognising that empirical data limitations hinder parameterisation of detailed models of estuarine ecosystem responses to multiple stressors (suspended sediment, sediment mud and metal content, and nitrogen inputs), an expert driven Bayesian network (BN) was developed and validated. Overall, trends in estuarine condition predicted by the BN model were well supported by field observations, including results that were markedly higher than random (71-84% concordance), providing confidence in the overall model dynamics. The general BN framework was then applied to a case study estuary to demonstrate the model's utility for informing management decisions. Results indicated that reductions in suspended sediment loading were likely to result in improvements in estuarine condition, which was further improved by reductions in sediment mud and metal content, with an increased likelihood of high abundance of ecological communities relative to baseline conditions. Notably, reductions in suspended sediment were also associated with an increased probability of high nuisance macroalgae and phytoplankton if nutrient loading was not also reduced (associated with increased water column light penetration). Our results highlight that if stressor limit setting is to be implemented, limits must incorporate ecosystem responses to cumulative stressors, consider the present and desired future condition of the estuary of interest, and account for the likelihood of unexpected ecological outcomes regardless of whether the experts (or empirical data) suggest a threshold has or has not been triggered.

An evaluation of continuous subcutaneous infusions across seven NHS acute hospitals: is there potential for 48-hour infusions?

BACKGROUND: Continuous subcutaneous infusions (CSCIs) are commonly used in the United Kingdom as a way of administering medication to patients requiring symptom control when the oral route is compromised. These infusions are typically administered over 24 h due to currently available safety data. The ability to deliver prescribed medication by CSCI over 48 h may have numerous benefits in both patient care and health service resource utilisation. This service evaluation aims to identify the frequency at which CSCI prescriptions are altered at NHS Acute Hospitals. METHODS: Pharmacists or members of palliative care teams at seven acute NHS hospitals recorded anonymised prescription data relating to the drug combination(s), doses, diluent and compatibility of CSCIs containing two or more drugs on a daily basis for a minimum of 2 days, to a maximum of 7 days. RESULTS: A total of 1301 prescriptions from 288 patients were recorded across the seven sites, yielding 584 discrete drug combinations. Of the 584 combinations, 91% (n = 533) included an opioid. The 10 most-common CSCI drug combinations represented 37% of the combinations recorded. Median duration of an unchanged CSCI prescription across all sites was 2 days. CONCLUSION: Data suggests medication delivered by CSCI over 48 h may be a viable option. Before a clinical feasibility study can be undertaken, a pharmacoeconomic assessment and robust chemical and microbiological stability data will be required, as will the assessment of the perceptions from clinical staff, patients and their families on the acceptability of such a change in practice.

Identification of C-Terminal Binding Protein 1 as a Novel NMDA Receptor Interactor.

A new N-methyl D aspartate neurotransmitter receptor interacting protein has been identified by yeast two-hybrid screening of a mouse brain cDNA library. C-terminal binding protein 1 (CtBP1) was shown to associate with the intracellular C-terminal regions of the N-methyl D aspartate receptor subunits GluN2A and GluN2D but not with GluN1-1a cytoplasmic C-terminal region. In yeast mating assays using a series of GluN2A C-terminal truncations, it was demonstrated that the CtBP1 binding domain was localized to GluN2A 1157-1382. The GluN2A binding domain was identified to lie within the CtBP1 161-224 region. CtBP1 co-immunoprecipitated with assembled GluN1/GluN2A receptors expressed in mammalian cells and also, in detergent extracts of adult mouse brain. Co-expression of CtBP1 with GluN1/GluN2A resulted in a significant decrease in receptor cell surface expression. The family of C-terminal binding proteins function primarily as transcriptional co-repressors. However, they are also known to modulate intracellular membrane trafficking mechanisms. Thus the results reported herein describe a putative role for CtBP1 in the regulation of cell surface N-methyl D aspartate receptor expression.

Developmental changes in trak-mediated mitochondrial transport in neurons.

Previous studies established that the kinesin adaptor proteins, TRAK1 and TRAK2, play an important role in mitochondrial transport in neurons. They link mitochondria to kinesin motor proteins via a TRAK acceptor protein in the mitochondrial outer membrane, the Rho GTPase, Miro. TRAKs also associate with enzyme, O-linked N-acetylglucosamine transferase (OGT), to form a quaternary, mitochondrial trafficking complex. A recent report suggested that TRAK1 preferentially controls mitochondrial transport in axons of hippocampal neurons whereas TRAK2 controls mitochondrial transport in dendrites. However, it is not clear whether the function of any of these proteins is exclusive to axons or dendrites and if their mechanisms of action are conserved between different neuronal populations and also, during maturation. Here, a comparative study was carried out into TRAK-mediated mitochondrial mobility in axons and dendrites of hippocampal and cortical neurons during maturation in vitro using a shRNA gene knockdown approach. It was found that in mature hippocampal and cortical neurons, TRAK1 predominantly mediates axonal mitochondrial transport whereas dendritic transport is mediated via TRAK2. In young, maturing neurons, TRAK1 and TRAK2 contribute similarly in mitochondrial transport in both axons and dendrites in both neuronal types. These findings demonstrate maturation regulation of mitochondrial transport which is conserved between at least two distinct neuronal subtypes.

APLP1 and APLP2, members of the APP family of proteins, behave similarly to APP in that they associate with NMDA receptors and enhance NMDA receptor surface expression.

The function of amyloid precursor protein (APP) is unknown, although the discovery that it contributes to the regulation of surface expression of N-methyl-D-aspartate (NMDA) receptors has afforded new insights into its functional significance. Since APP is a member of a gene family that contains two other members, amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2), it is important to determine if the related APP proteins possess the same properties as APP with respect to their interactions with NMDA receptors. Following expression in mammalian cells, both APLP1 and APLP2 behaved similarly to APP in that they both co-immunoprecipitated with the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B, via interaction with the obligatory GluN1 subunit. Immunoprecipitations from detergent extracts of adult mammalian brain showed co-immunoprecipitation of APLP1 and APLP2 with GluN2A- and GluN2B-containing NMDA receptors. Furthermore, similarly to APP, APLP1 and APLP2 both enhanced GluN1/GluN2A and GluN1/GluN2B cell surface expression. Thus, all the three members of the APP gene family behave similarly in that they each contribute to the regulation of cell surface NMDA receptor homoeostasis. Amyloid precursor protein (APP) has been shown to associate with N-methyl-d-aspartate (NMDA) receptors and to enhance their cell surface expression. Here, we show that the other members of the APP family, APLP1 and APLP2, behave similarly to APP in that they both associate with assembled NMDA receptors in the endoplasmic reticulum via their interaction with the NMDA receptor subunit, GluN1 and, they enhance receptor cell surface expression. Alternative scenarios are depicted since it is to be determined if respective associations are direct.

Localization of the kinesin adaptor proteins trafficking kinesin proteins 1 and 2 in primary cultures of hippocampal pyramidal and cortical neurons.

Neuronal function requires regulated anterograde and retrograde trafficking of mitochondria along microtubules by using the molecular motors kinesin and dynein. Previous work has established that trafficking kinesin proteins (TRAKs),TRAK1 and TRAK2, are kinesin adaptor proteins that link mitochondria to kinesin motor proteins via an acceptor protein in the mitochondrial outer membrane, etc. the Rho GTPase Miro. Recent studies have shown that TRAK1 preferentially controls mitochondrial transport in axons of hippocampal neurons by virtue of its binding to both kinesin and dynein motor proteins, whereas TRAK2 controls mitochondrial transport in dendrites resulting from its binding to dynein. This study further investigates the subcellular localization of TRAK1 and TRAK2 in primary cultures of hippocampal and cortical neurons by using both commercial antibodies and anti-TRAK1 and anti-TRAK2 antibodies raised in our own laboratory (in-house). Whereas TRAK1 was prevalently localized in axons of hippocampal and cortical neurons, TRAK2 was more prevalent in dendrites of hippocampal neurons. In cortical neurons, TRAK2 was equally distributed between axons and dendrites. Some qualitative differences were observed between commercial and in-house-generated antibody immunostaining.

Revisiting the TRAK family of proteins as mediators of GABAA receptor trafficking.

γ-Aminobutyric acid type A (GABAA) receptor interacting factor-1 (GRIF-1) was originally discovered as a result of studies aiming to find the elusive GABAA receptor clustering protein. It was identified as a GABAA receptor associated protein by virtue of its specific interaction with the GABAA receptor ß2 subunit intracellular loop in a yeast two-hybrid screen of a rat brain cDNA library. Further work however, established that GRIF-1, now known as trafficking kinesin protein 2 (TRAK2), is a member of the TRAK family of kinesin adaptor proteins. A pivotal role for TRAK1 and TRAK2 in the transport of mitochondria is well recognized. Notwithstanding this progress, there is a body of evidence that still supports a role for TRAKs in the intracellular transport of GABAA receptors. This is critically reviewed in this article.

Introduction to thematic minireview series on celebrating the discovery of the cysteine loop ligand-gated ion channel superfamily.

The year 2012 marks the 25th anniversary of the discovery of the Cys loop ligand-gated ion channel superfamily of neurotransmitter receptors. This minireview series celebrates this with a series of articles reviewing current information for each of the family members, nicotinic acetylcholine receptors, glycine receptors, GABA(A) receptors, serotonin-3 (5-HT(3)) receptors, and glutamate-gated chloride ion channels of proteasome invertebrate phyla.

Identification of N-methyl-D-aspartic acid (NMDA) receptor subtype-specific binding sites that mediate direct interactions with scaffold protein PSD-95.

N-methyl-D-aspartate (NMDA) neurotransmitter receptors and the postsynaptic density-95 (PSD-95) membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins are integral components of post-synaptic macromolecular signaling complexes that serve to propagate glutamate responses intracellularly. Classically, NMDA receptor NR2 subunits associate with PSD-95 MAGUKs via a conserved ES(E/D)V amino acid sequence located at their C termini. We previously challenged this dogma to demonstrate a second non-ES(E/D)V PSD-95-binding site in both NMDA receptor NR2A and NR2B subunits. Here, using a combination of co-immunoprecipitations from transfected mammalian cells, yeast two-hybrid interaction assays, and glutathione S-transferase (GST) pulldown assays, we show that NR2A subunits interact directly with PSD-95 via the C-terminal ESDV motif and additionally via an Src homology 3 domain-binding motif that associates with the Src homology 3 domain of PSD-95. Peptide inhibition of co-immunoprecipitations of NR2A and PSD-95 demonstrates that both the ESDV and non-ESDV sites are required for association in native brain tissue. Furthermore, we refine the non-ESDV site within NR2B to residues 1149-1157. These findings provide a molecular basis for the differential association of NMDA receptor subtypes with PSD-95 MAGUK scaffold proteins. These selective interactions may contribute to the organization, lateral mobility, and ultimately the function of NMDA receptor subtypes at synapses. Furthermore, they provide a more general molecular mechanism by which the scaffold, PSD-95, may discriminate between potential interacting partner proteins.

Neto1 associates with the NMDA receptor/amyloid precursor protein complex.

Neuropilin tolloid-like 1 (Neto1), is a CUB domain-containing transmembrane protein that was recently identified as a novel component of the NMDA receptor complex. Here, we have investigated the possible association of Neto1 with the amyloid precursor protein (APP)695/GluN1/GluN2A and APP695/GluN1/GluN2B NMDA receptor trafficking complexes that we have previously identified. Neto1(HA) was shown to co-immunoprecipitate with assembled NMDA receptors via GluN2A or GluN2B subunits; Neto1(HA) did not co-immunoprecipitate APP695(FLAG) . Co-immunoprecipitations from mammalian cells co-transfected with APP695(FLAG) , Neto1(HA) and GluN1/GluN2A or GluN1/GluN2B revealed that all four proteins co-exist within one macromolecular complex. Immunoprecipitations from native brain tissue similarly revealed the existence of a GluN1/GluN2A or GluN2B/APP/Neto1 complex. Neto1(HA) caused a reduction in the surface expression of both NMDA receptor subtypes, but had no effect on APP695(FLAG) - or PSD-95α(c-Myc) enhanced surface receptor expression. The Neto1 binding domain of GluN2A was mapped using GluN1/GluN2A chimeras and GluN2A truncation constructs. The extracellular GluN2A domain does not contribute to association with Neto1(HA) but deletion of the intracellular tail resulted in a loss of Neto-1(HA) co-immunoprecipitation which was paralleled by a loss of association between GluN2A and SAP102. Thus, Neto1 is concluded to be a component of APP/NMDA receptor trafficking complexes.

GABA(A) receptors can initiate the formation of functional inhibitory GABAergic synapses.

The mechanisms that underlie the selection of an inhibitory GABAergic axon's postsynaptic targets and the formation of the first contacts are currently unknown. To determine whether expression of GABAA receptors (GABAA Rs) themselves--the essential functional postsynaptic components of GABAergic synapses--can be sufficient to initiate formation of synaptic contacts, a novel co-culture system was devised. In this system, the presynaptic GABAergic axons originated from embryonic rat basal ganglia medium spiny neurones, whereas their most prevalent postsynaptic targets, i.e., α1/ß2/γ2-GABAA Rs, were expressed constitutively in a stably transfected human embryonic kidney 293 (HEK293) cell line. The first synapse-like contacts in these co-cultures were detected by colocalization of presynaptic and postsynaptic markers within 2 h. The number of contacts reached a plateau at 24 h. These contacts were stable, as assessed by live cell imaging; they were active, as determined by uptake of a fluorescently labelled synaptotagmin vesicle-luminal domain-specific antibody; and they supported spontaneous and action potential-driven postsynaptic GABAergic currents. Ultrastructural analysis confirmed the presence of characteristics typical of active synapses. Synapse formation was not observed with control or N-methyl-d-aspartate receptor-expressing HEK293 cells. A prominent increase in synapse formation and strength was observed when neuroligin-2 was co-expressed with GABAA Rs, suggesting a cooperative relationship between these proteins. Thus, in addition to fulfilling an essential functional role, postsynaptic GABAA Rs can promote the adhesion of inhibitory axons and the development of functional synapses.

Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins.

The relative content of NR2 subunits in the NMDA receptor confers specific signaling properties and plasticity to synapses. However, the mechanisms that dynamically govern the retention of synaptic NMDARs, in particular 2A-NMDARs, remain poorly understood. Here, we investigate the dynamic interaction between NR2 C termini and proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) scaffold proteins at the single molecule level by using high-resolution imaging. We report that a biomimetic divalent competing ligand, mimicking the last 15 amino acids of NR2A C terminus, specifically and efficiently disrupts the interaction between 2A-NMDARs, but not 2B-NMDARs, and PDZ proteins on the time scale of minutes. Furthermore, displacing 2A-NMDARs out of synapses lead to a compensatory increase in synaptic NR2B-NMDARs, providing functional evidence that the anchoring mechanism of 2A- or 2B-NMDARs is different. These data reveal an unexpected role of the NR2 subunit divalent arrangement in providing specific anchoring within synapses, highlighting the need to study such dynamic interactions in native conditions.

Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons.

In neurons, the proper distribution of mitochondria is essential because of a requirement for high energy and calcium buffering during synaptic neurotransmission. The efficient, regulated transport of mitochondria along axons to synapses is therefore crucial for maintaining function. The trafficking kinesin protein (TRAK)/Milton family of proteins comprises kinesin adaptors that have been implicated in the neuronal trafficking of mitochondria via their association with the mitochondrial protein Miro and kinesin motors. In this study, we used gene silencing by targeted shRNAi and dominant negative approaches in conjunction with live imaging to investigate the contribution of endogenous TRAKs, TRAK1 and TRAK2, to the transport of mitochondria in axons of hippocampal pyramidal neurons. We report that both strategies resulted in impairing mitochondrial mobility in axonal processes. Differences were apparent in terms of the contribution of TRAK1 and TRAK2 to this transport because knockdown of TRAK1 but not TRAK2 impaired mitochondrial mobility, yet both TRAK1 and TRAK2 were shown to rescue transport impaired by TRAK1 gene knock-out. Thus, we demonstrate for the first time the pivotal contribution of the endogenous TRAK family of kinesin adaptors to the regulation of mitochondrial mobility.

N-acetylglucosamine transferase is an integral component of a kinesin-directed mitochondrial trafficking complex.

Trafficking kinesin proteins (TRAKs) 1 and 2 are kinesin-associated proteins proposed to function in excitable tissues as adaptors in anterograde trafficking of cargoes including mitochondria. They are known to associate with N-acetylglucosamine transferase and the mitochondrial rho GTPase, Miro. We used confocal imaging, Förster resonance energy transfer and immunoprecipitations to investigate association between TRAKs1/2, N-acetylglucosamine transferase, the prototypic kinesin-1, KIF5C, and Miro. We demonstrate that in COS-7 cells, N-acetylglucosamine transferase, KIF5C and TRAKs1/2 co-distribute. Förster resonance energy transfer was observed between N-acetylglucosamine transferase and TRAKs1/2. Despite co-distributing with KIF5C and immunoprecipitations demonstrating a TRAK1/2, N-acetylglucosamine transferase and KIF5C ternary complex, no Förster resonance energy transfer was detected between N-acetylglucosamine transferase and KIF5C. KIF5C, N-acetylglucosamine transferase, TRAKs1/2 and Miro formed a quaternary complex. The presence of N-acteylglucosamine transferase partially prevented redistribution of mitochondria induced by trafficking proteins 1/2 and KIF5C. TRAK2 was a substrate for N-acetylglucosamine transferase with TRAK2 (S562) identified as a site of O-N-acetylglucosamine modification. These findings substantiate trafficking kinesin proteins as scaffolds for the formation of a multi-component complex involved in anterograde trafficking of mitochondria. They further suggest that O-glycosylation may regulate complex formation.

Simple wound care facilitates full healing in post-earthquake Haiti.

The author provides an insight into the basic health care needs of two spinal cord injury patients who were cared for in a specially set up 25-bedded spinal cord injury unit in Haiti. While focusing on their extreme wound care requirements, the author highlights the need for adequate fluid, nutrition, hygiene and aseptic technique. Both patients were victims of the January 2010 earthquake in Port au Prince, Haiti. The author describes the basic wound care strategy for a patient with a category IV sacral pressure ulcer and another with a broken down thoracic spine surgical wound with visible metal work. This article describes how simple wound care effected the complete healing of large sacral pressure ulcers and broken down spinal surgical wounds without the need for further surgical intervention.

GTPase dependent recruitment of Grif-1 by Miro1 regulates mitochondrial trafficking in hippocampal neurons.

The transport of mitochondria to specific neuronal locations is critical to meet local cellular energy demands and for buffering intracellular calcium. A critical role for kinesin motor proteins in mitochondrial transport in neurons has been demonstrated. Currently however the molecular mechanisms that underlie the recruitment of motor proteins to mitochondria, and how this recruitment is regulated remain unclear. Here we show that a protein trafficking complex comprising the adaptor protein Grif-1 and the atypical GTPase Miro1 can be detected in mammalian brain where it is localised to neuronal mitochondria. Increasing Miro1 expression levels recruits Grif-1 to mitochondria. This results in an enhanced transport of mitochondria towards the distal ends of neuronal processes. Uncoupling Grif-1 recruitment to mitochondria by expressing a Grif-1/Miro1 binding fragment dramatically reduces mitochondrial transport into neuronal processes. Altering Miro1 function by mutating its first GTPase domain affects Miro's ability to recruit Grif-1 to mitochondria and in addition alters mitochondrial distribution and shape along neuronal processes. These data suggest that Miro1 and the kinesin adaptor Grif-1 play an important role in regulating mitochondrial transport in neurons.

Amyloid precursor protein 695 associates with assembled NR2A- and NR2B-containing NMDA receptors to result in the enhancement of their cell surface delivery.

This is a study of the interaction between the two NMDA neurotransmitter receptor subtypes, NR1/NR2A and NR1/NR2B, and amyloid precursor protein (APP) 695, the major APP variant expressed in neurones. APP695 co-immunoprecipitated with assembled NR1-1a/NR2A and NR1-1a/NR2B NMDA receptors following expression in mammalian cells. Single NR1-1a, NR1-2a, NR1-4b(c-Myc), or NR2 subunit transfections revealed that co-association of APP695 with assembled NMDA receptors was mediated via the NR1 subunit; it was independent of the NR1 C1, C2, and C2' cassettes and, the use of an NR1-2a(c-Myc)-trafficking mutant suggested that interaction between the two proteins occurs in the endoplasmic reticulum. The use of antibodies directed against extracellular and intracellular NR2 subunit epitopes for immunoprecipitations suggested that APP/NMDA receptor association was mediated via N-terminal domains. Anti-APP antibodies immunoprecipitated NR1, NR2A, and NR2B immunoreactive bands from detergent extracts of mammalian brain; reciprocally, anti-NR1 or anti-NR2A antibodies co-immunoprecipitated APP immunoreactivity. Immune pellets from brain were sensitive to endoglycosidase H suggesting that, as for heterologous expression, APP and NMDA receptor association occurs in the endoplasmic reticulum. Co-expression of APP695 in mammalian cells resulted in enhanced cell surface expression of both NR1-1a/NR2A and NR1-1a/NR2B NMDA receptors with no increase in total subunit expression. These findings are further evidence for a role of APP in intracellular trafficking mechanisms. Further, they provide a link between two major brain proteins that have both been implicated in Alzheimer's disease.