Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer’s disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models.

Synaptic dysfunction is an early mechanism in Alzheimer’s disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. Here we show that Aβ released by microglia in association with large extracellular vesicles (Aβ-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex-dentate gyrus circuitry. 1 h after Aβ-EV injection into the mouse entorhinal cortex, long-term potentiation (LTP) was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was impaired also in the dentate gyrus, revealing a spreading of LTP deficit between the two regions. Similar results were obtained upon injection of EVs carrying Aβ naturally secreted by CHO7PA2 cells, while neither Aβ42alone nor inflammatory EVs devoid of Aβ were able to propagate LTP impairment. Using optical tweezers combined to time-lapse imaging to study Aβ-EV-neuron interaction, we show that Aβ-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aβ-EV motility was inhibited, no propagation of LTP deficit occurred along the entorhinal-hippocampal circuit, implicating large EV motion at the neuron surface in the spreading of LTP impairment. Our data indicate the involvement of large microglial EVs in the rise and propagation of early synaptic dysfunction in Alzheimer’s disease, and suggest a new mechanism controlling the diffusion of large EVs and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

Laparoscopic major hepatectomies are safe and feasible procedures allowing a similar complication rate with a shorter hospital stay and diminished postoperative pain with respect to the standard approach.

Perineuronal nets (PNNs) surround specific neurons in the brain and are involved in various forms of plasticity and clinical conditions. However, our understanding of the PNN role in these phenomena is limited by the lack of highly quantitative maps of PNN distribution and association with specific cell types. Here, we present the first comprehensive atlas of PNN distribution (in Allen Brain Atlas coordinates) and colocalization with parvalbumin (PV) cells for over 600 regions of the adult mouse brain. Data analysis showed that PV expression is a good predictor of PNN aggregation. In the cortex, PNNs are dramatically enriched in layer 4 of all primary sensory areas in correlation with thalamocortical input density, and their distribution mirrors intracortical connectivity patterns. Gene expression analysis identified many PNN correlated genes. Strikingly, PNN anticorrelated transcripts were enriched in synaptic plasticity genes, generalizing PNN role as circuit stability factors. Overall, this atlas offers novel resources for understanding the organizational principles of the brain extracellular matrix.

Various reperfused human cadaver models exist, enabling practise of mainly vascular procedures. Preservation method determines the level of simulation fidelity. Thorough evaluation of these models as surgical training tools and transfer effectiveness is still lacking.