Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α∆-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α∆-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.post-print1848 K

Astrocytic p38α MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory.

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca2+ signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.post-print5316 K

Regulation of cell death by sphingosine 1-phosphate lyase.

International audienceBy controlling sphingosine 1-phosphate (S1P) catabolism, S1P lyase (SPL) represents an undeniable candidate as potential regulator of a cancer cell's fate in response to stress. Our recent study reveals that complete loss of SPL activity leads to upregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and consequently protects against apoptosis induced by chemotherapy and nutrient starvation but not against autophagy. Here, we speculate on how S1P and disruption of S1P breakdown may regulate cell death and autophagy

Functions of sphingolipid metabolism in mammals--lessons from genetic defects.

International audienceMuch is known about the pathways that control the biosynthesis, transport and degradation of sphingolipids. During the last two decades, considerable progress has been made regarding the roles this complex group of lipids play in maintaining membrane integrity and modulating responses to numerous signals. Further novel insights have been provided by the analysis of newly discovered genetic diseases in humans as well as in animal models harboring mutations in the genes whose products control sphingolipid metabolism and action. Through the description of the phenotypic consequences of genetic defects resulting in the loss of activity of the many proteins that synthesize, transport, bind, or degrade sphingolipids, this review summarizes the (patho)physiological functions of these lipids

Astrocytic p38 MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.We thank the personnel at the fluorescence microscopy facility of the CBMSO (SMOC) for their expert technical assistance. We also thank Alfonso Araque, Carlos Dotti, Liset Menéndez de la Prida, Manuel Valero, Sara Mederos and Gertrudis Perea for expert advice and critical reading of the manuscript, and Simon Arthur (University of Dundee, UK) for the p38α knockout mice. We thank Godwin K. Dogbevia, Artur Luzgin, and Maria Calleja for technical help with molecular biology, virus purifications and characterization of AAV2/1-PGFAP-TeTxLC-2A-mKO. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness to J.A.E. (SAF2015-72988-EXP, PCIN-2016-095 and SAF2017-86983-R), to M.N. (SAF2014-58598-JIN; RYC-2016-20414), to M.I.C. (IJCI-2015-25507), and to J.A.E. and A.R.N. (CSD2010-0045). M.N. was also funded from BBVA Foundation and L'Oreal Unesco “For Women in Science”

Neuronal p38α mediates age‐associated neural stem cell exhaustion and cognitive decline

Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age. By using mice expressing p38α-lox and CamkII-Cre alleles (p38α∆-N), we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged p38α∆-N mice present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline.Instituto de Salud Carlos III, Grant/Award Number: CP16/00039, PI13/02277 and PI16/01580; FEDER Funds; Spanish Ministry of Economy and Competitiveness (MINECO), Grant/Award Number: CSD2010‐0045 and SAF2016‐78114‐R; CIBERFES, Grant/Award Number: CB16/10/0028