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 amyloid-β 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. One hour after Aβ-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aβ naturally secreted by CHO7PA2 cells, while neither Aβ₄₂ alone nor inflammatory extracellular vesicles devoid of Aβ were able to propagate long-term potentiation 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 long-term potentiation deficit occurred along the entorhinal–hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment. Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer’s disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

The Entorhinal cortex (EC) has been implicated in the early stages of Alzheimer’s disease (AD). In particular, spreading of neuronal dysfunction within the EC-Hippocampal network has been suggested. We have investigated the time course of EC dysfunction in the AD mouse model carrying human mutation of amyloid precursor protein (mhAPP) expressing human Aβ. We found that in mhAPP mice plasticity impairment is first observed in EC superficial layer and further affected with time. A selective impairment of LTP was observed in layer II horizontal connections of EC slices from 2 month old mhAPP mice, whereas at later stage of neurodegeneration (6 month) basal synaptic transmission and LTD were also affected. Accordingly, early synaptic deficit in the mhAPP mice were associated with a selective impairment in EC-dependent associative memory tasks. The introduction of the dominant-negative form of RAGE lacking RAGE signalling targeted to microglia (DNMSR) in mhAPP mice prevented synaptic and behavioural deficit, reducing the activation of stress related kinases (p38MAPK and JNK). Our results support the involvement of the EC in the development and progression of the synaptic and behavioural deficit during amyloid-dependent neurodegeneration and demonstrate that microglial RAGE activation in presence of Aβ-enriched environment contributes to the EC vulnerability.

Genetic and biological studies provide strong support for the hypothesis that accumulation of beta amyloid peptide (Abeta) contributes to the etiology of Alzheimer's disease (AD). Growing evidence indicates that oligomeric soluble Abeta plays an important role in the development of synaptic dysfunction and the impairment of cognitive function in AD. The receptor for advanced glycation end products (RAGE), a multiligand receptor in the immunoglobulin superfamily, acts as a cell surface binding site for Abeta and mediates alternations in the phosphorylation state of mitogen-activated protein kinase (MAPKs). Recent results have shown that MAPKs are involved in neurodegenerative processes. In particular, changes in the phosphorylation state of various MAPKs by Abeta lead to synaptic dysfunction and cognitive decline, as well as development of inflammatory responses in AD. The present review summarizes the evidence justifying a novel therapeutic approach focused on inhibition of RAGE signaling in order to arrest or halt the development of neuronal dysfunction in AD.

Ischemia is known to increase the deleterious effect of β-amyloid (Aβ), contributing to early cognitive impairment in Alzheimer9s disease. Here, we investigated whether transient ischemia may function as a trigger for Aβ-dependent synaptic impairment in the entorhinal cortex (EC), acting through specific cellular signaling. We found that synaptic depression induced by oxygen glucose deprivation (OGD) was enhanced in EC slices either in presence of synthetic oligomeric Aβ or in slices from mutant human amyloid precursor protein transgenic mice (mhAPP J20). OGD-induced synaptic depression was ameliorated by functional suppression of RAGE. In particular, overexpression of the dominant-negative form of RAGE targeted to microglia (DNMSR) protects against OGD-induced synaptic impairment in an amyloid-enriched environment, reducing the activation of stress-related kinases (p38MAPK and JNK) and the release of IL-1β. Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by Aβ and triggered by transient ischemia.

The central nervous system architecture is highly dynamic and continuously modified by sensory experience through processes of neuronal plasticity. Plasticity is achieved by a complex interplay of environmental influences and physiological mechanisms that ultimately activate intracellular signal transduction pathways regulating gene expression. In addition to the remarkable variety of transcription factors and their combinatorial interaction at specific gene promoters, epigenetic mechanisms that regulate transcription have emerged as conserved processes by which the nervous system accomplishes the induction of plasticity. Experience-dependent changes of DNA methylation patterns and histone posttranslational modifications are, in fact, recruited as targets of plasticity-associated signal transduction mechanisms. Here, we shall concentrate on structural and functional consequences of early sensory deprivation in the visual system and discuss how intracellular signal transduction pathways associated with experience regulate changes of chromatin structure and gene expression patterns that underlie these plastic phenomena. Recent experimental evidence for mechanisms of cross-modal plasticity following congenital or acquired sensory deprivation both in human and animal models will be considered as well. We shall also review different experimental strategies that can be used to achieve the recovery of sensory functions after long-term deprivation in humans.