Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations
Jessica Brown, Elena Camporesi, Juan Lantero-Rodriguez, Maria Olsson, Alice Wang, Blanca Medem, Henrik Zetterberg, Kaj Blennow, Thomas K. Karikari, Mark Wall and Emily Hill
Alzheimer’s disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input–output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.
ATP-mediated signalling in the central synapses
Ulyana Lalo, Yuriy Pankratov
ATP released from the synaptic terminals and astrocytes can activate neuronal P2 receptors at a variety of locations across the CNS. Although the postsynaptic ATP-mediated signalling does not bring a major contribution into the excitatory transmission, it is instrumental for slow and diffuse modulation of synaptic dynamics and neuronal firing in many CNS areas. Neuronal P2X and P2Y receptors can be activated by ATP released from the synaptic terminals, astrocytes and microglia and thereby can participate in the regulation of synaptic homeostasis and plasticity. There is growing evidence of importance of purinergic regulation of synaptic transmission in different physiological and pathological contexts. Here, we review the main mechanisms underlying the complexity and diversity of purinergic signalling and purinergic modulation in central neurons.
Characterization of a TatA/TatB binding site on the TatC component of the Escherichia coli twin arginine translocase
Emmanuele Severi, Mariana Bunoro Batista, Adelie Lannoy, Phillip J Stansfeld, Tracy Palmer
In Escherichia coli and other Gram-negative bacteria, the Tat machinery comprises TatA, TatB and TatC components. A Tat receptor complex, formed from all three proteins, binds Tat substrates, which triggers receptor organization and recruitment of further TatA molecules to form the active Tat translocon. The polytopic membrane protein TatC forms the core of the Tat receptor and harbours two binding sites for the sequence-related TatA and TatB proteins. A 'polar' cluster binding site, formed by TatC transmembrane helices (TMH) 5 and 6 is occupied by TatB in the resting receptor and exchanges for TatA during receptor activation. The second binding site, lying further along TMH6, is occupied by TatA in the resting state, but its functional relevance is unclear. Here we have probed the role of this second binding site through a programme of random and targeted mutagenesis. While it is not clear whether TatA binding at the TMH6 site is essential for Tat activity, the isolation of inactivating substitutions indicates that this region of the protein has a critical function.
The mammalian purine salvage pathway as an exploitable route for cerebral bioenergetic support after brain injury
Philipp Gessner, Jenni Lum, Bruno G Frenguelli
Purine-based molecules play ancient, fundamental, and evolutionarily-conserved roles across life on Earth, ranging from DNA and RNA, to the universal energy currency, ATP. Having previously shown that hippocampal cellular ATP and adenosine release can be increased by supplying substrates for the PSP (d-ribose and adenine), we now explore the expression of DNPB and PSP enzymes in hippocampal neurons and astrocytes based on available transcriptomic data. We find that key enzymes of the PSP are expressed at higher levels than those in the DNPB pathway, and that PSP enzymes are expressed at higher levels in neurons than in astrocytes. These data reflect the importance of the PSP in the mammalian brain and imply that pharmacological targeting of the PSP may be particularly beneficial to neurons at times of metabolic stress.
Dialysis adequacy and hemoglobin levels predict cerebral atrophy in maintenance-hemodialysis patients
Cao M.X., Xiao J., Qin H.-M., Wang Z.H., Boltze J., Liu, S.X., Li S.
This study aims to investigate the factors influencing cerebral atrophy (CA) and to derive a CA prediction nomogram in maintenance-hemodialysis patients. First, brain volumes of hemodialysis patients (≤55 years) were compared against age- and sex-matched healthy controls, and differences were revealed in bilateral insular cisterns width, maximum cerebral sulci width, Evans index, ventricular-brain ratio, frontal atrophy index, and temporal lobe ratio. Then, the patients were divided equally into "no or mild" or "severe" CA groups. Potential factors influencing CA were screened. Kt/V (urea removal index) and hemoglobin levels negatively correlated with CA degree, and were used to establish a nomogram within randomly assigned training and validation patient groups.. The nomogram had optimal AUROC for training (0.759) and validation (0.804) groups when albumin was also included. Hemodialysis patients showed reduced anterior brain volumes and the nomogram established herein may have predictive value for developing CA.
IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
Khan, Shakil, Patra, Pabitra H., Somerfield, Hannah, Benya-Aphikul, Hattaya, Upadhya, Manoj and Zhang, Xuming
TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ-motif containing GTPase activating protein 1 (IQGAP1) is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQGAP1 bind to each other and are highly colocalised in sensory DRG neurons in mice. The expression of IQGAP1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of DRG neurons catalysed by the small GTPase Cdc42 associated with IQGAP1, leading to functional sensitization of the channel. Activation of PKA is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQGAP1. Concordantly, deletion of IQGAP1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQGAP1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels.