Cellular senescence at the crossroads of inflammation and Alzheimer's disease

Aging is a key risk factor for Alzheimer's disease (AD), but the reasons for this association are not well understood. Senescent cells accumulate in aged tissues and have been shown to play causal roles in age-related pathologies through their proinflammatory secretome. The question arises whether senescence-induced inflammation might contribute to AD and bridge the gap between aging and AD. Here, we highlight the role of cellular senescence as a driver of the aging phenotype, and discuss the current evidence that connects senescence with AD and neurodegeneration

Astrocyte Ca2+-evoked ATP release regulates myelinated axon excitability and conduction speed

INTRODUCTION: Astrocytes support neuronal function throughout the central nervous system. In the gray matter, they regulate synapse number during development, remove synaptically released neurotransmitters to terminate their action and prevent excitotoxicity, control the extracellular potassium concentration to prevent hyperexcitability, regulate blood flow to ensure an adequate energy supply, provide lactate to neurons for energy, and respond to rises of intracellular calcium concentration ([Ca2+]i) by releasing adenosine triphosphate (ATP) and other gliotransmitters that act on neuronal receptors to modulate information processing. However, their role is unclear in the white matter, which transmits information rapidly between gray matter areas using axons wrapped with capacitance-reducing myelin (although they have been suggested to regulate myelination during development and during normal function). RATIONALE: Recently, it has been suggested that learning and memory may reflect not only changes in synaptic function in the gray matter, but also changes in white matter function. In particular, neural circuit function might be regulated by changes in the conduction speed of myelinated axons that result in an altered arrival time of action potentials at a distant neuron. These speed changes might be brought about by alterations of the properties of the passively conducting myelinated internodes or of the intervening excitable nodes of Ranvier, where the action potential is generated. We applied immunohistochemistry to assess how astrocytes interact with myelinated axons, neuronal stimulation and light-evoked calcium uncaging in astrocytes to evoke Ca2+-dependent release of gliotransmitters, and electrophysiology and pharmacology to characterize how astrocyte-released substances might affect the axon initial segment (AIS) and nodes of Ranvier of myelinated neurons. Measurements of conduction velocity and computer modeling allowed us to interpret the results. RESULTS: Astrocytes closely approach the axons of myelinated neurons in layer V of the cerebral cortex that enter the corpus callosum. Uncaging Ca2+ within astrocytes or stimulating spike trains in neurons evoked a rise of astrocyte [Ca2+]i that triggered the release of ATP-containing vesicles from these cells. This evoked an inward current in the AIS and nodes of Ranvier of the pyramidal neurons. Pharmacology showed that this was mediated by the activation of Gs-linked adenosine A2a receptors (A2aRs), implying that the released ATP was converted to adenosine by extracellular enzymes. The A2aRs raise the intracellular concentration of cyclic AMP, which activates hyperpolarization-activated cyclic nucleotide–gated (HCN) channels mediating the inward hyperpolarization-activated current (Ih) and thus depolarizes the cell. In the AIS, the activation of A2aRs alters excitability and hence action potential generation, whereas in the nodes of Ranvier, it decreases the conduction speed of the action potential along the axon. CONCLUSION: As in the gray matter, astrocyte [Ca2+]i regulates the release of ATP into the extracellular space in the white matter. After conversion to adenosine, this regulates the excitability and conduction speed of myelinated axons. The changes in excitability at the AIS will lead to changes in the relationship between the synaptic input and action potential output of the cell. The altered conduction speed of the myelinated axon may change neural circuit function by changing the action potential arrival time at the cell’s output synapses, thus altering the integration of signals in postsynaptic neurons. Variations in astrocyte-derived adenosine level can occur between wake and sleep states, and the extracellular adenosine concentration rises during energy deprivation conditions. These changes in adenosine level could thus control white matter information flow and neural circuit function

Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery

Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and Endoplasmic Reticulum-Mitochondria Contacts Sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality

Molecular Sites for the Positive Allosteric Modulation of Glycine Receptors by Endocannabinoids

Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α1, α2 and α3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α1 GlyRs but inhibit α2 and α3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine the positive modulation of α1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α1 GlyRs, without affecting inhibition of α2 and α3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain

Molecular and functional heterogeneity of GABAergic synapses

Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses