Targeting Synaptic Plasticity in Experimental Models of Alzheimer’s Disease

Mango, Dalila; Saidi, Amira; Cisale, Giusy Ylenia; Feligioni, Marco; Corbo, Massimo; Nisticò, Robert

doi:10.3389/fphar.2019.00778

Cited by 87 publications

(53 citation statements)

References 94 publications

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“…Hippocampal LTP occurs during hippocampus-dependent learning and memory (Bliss et al, 2018) and its reduction is linked to memory loss in mouse models of Alzheimer's disease (Mango et al, 2019). Facilitation of LTP induction by XE991 (Song et al, 2009;Fontan-Lozano et al, 2011;Petrovic et al, 2012) suggests that pharmacologic K v 7 inhibition may enhance learning and memory.…”

Section: Role Of K V 7 Channels In Hippocampus-dependent Learning Andmentioning

confidence: 99%

The Role of Kv7 Channels in Neural Plasticity and Behavior

2020

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Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are widely thought to underlie learning and memory. Voltage-gated KCNQ/K v 7 potassium channels have been of great interest as the potential targets for memory disorders due to the beneficial effects of their antagonists in cognition. Importantly, de novo dominant mutations in their neuronal subunits KCNQ2/K v 7.2 and KCNQ3/K v 7.3 are associated with epilepsy and neurodevelopmental disorder characterized by developmental delay and intellectual disability. The role of K v 7 channels in neuronal excitability and epilepsy has been extensively studied. However, their functional significance in neural plasticity, learning, and memory remains largely unknown. Here, we review recent studies that support the emerging roles of K v 7 channels in intrinsic and synaptic plasticity, and their contributions to cognition and behavior.

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Section: Role Of K V 7 Channels In Hippocampus-dependent Learning Andmentioning

confidence: 99%

The Role of Kv7 Channels in Neural Plasticity and Behavior

2020

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“…Therefore, the development of relevant experimental models will provide a more complete view of pathogenic processes in AD. Such opportunities may be possible in an in vitro amyloidosis model based on synthetic amyloid peptide application ( Stancu et al, 2014 ; Villalobos Acosta et al, 2018 ; Mango et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the β-Amyloidopathy Model in vitro

Митрошина

Yarkov

Mishchenko

et al. 2020

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is a widespread chronic neurodegenerative pathology characterized by synaptic dysfunction, partial neuronal death, cognitive decline and memory impairments. The major hallmarks of AD are extracellular senile amyloid plaques formed by various types of amyloid proteins (Aβ) and the formation and accumulation of intracellular neurofibrillary tangles. However, there is a lack of relevant experimental models for studying changes in neural network activity, the features of intercellular signaling or the effects of drugs on the functional activity of nervous cells during AD development. In this work, we examined two experimental models of amyloidopathy using primary hippocampal cultures. The first model involves the embryonic brains of 5xFAD mice; the second uses chronic application of amyloid beta 1-42 (Aβ1-42). The model based on primary hippocampal cells obtained from 5xFAD mice demonstrated changes in spontaneous network calcium activity characterized by a decrease in the number of cells exhibiting Ca 2+ activity, a decrease in the number of Ca 2+ oscillations and an increase in the duration of Ca 2+ events from day 21 of culture development in vitro . Chronic application of Aβ1-42 resulted in the rapid establishment of significant neurodegenerative changes in primary hippocampal cultures, leading to marked impairments in neural network calcium activity and increased cell death. Using this model and multielectrode arrays, we studied the influence of amyloidopathy on spontaneous bioelectrical neural network activity in primary hippocampal cultures. It was shown that chronic Aβ application decreased the number of network bursts and spikes in a burst. The spatial structure of neural networks was also disturbed that characterized by reduction in both the number of key network elements (hubs) and connections between network elements. Moreover, application of brain-derived neurotrophic factor (BDNF) recombinant protein and BDNF hyperexpression by an adeno-associated virus vector partially prevented these amyloidopathy-induced neurodegenerative phenomena. BDNF maintained cell viability and spontaneous bioelectrical and calcium network activity in primary hippocampal cultures.

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“…Thus, RL-118 treatment could prevent the loss of those neuroplasticity markers, in particular Synaptophysin (Mango et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis

Puigoriol-Illamola

Companys-Alemany

McGuire

et al. 2020

Preprint

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Taking into consideration the convergence of ageing, stress and neurodegenerative diseases, such as AD, there is impaired GC signalling. Therefore, the study of GC-mediated stress response to chronic moderate stressful situations, as account in daily life, becomes of huge interest to design pharmacological strategies to prevent neurodegeneration. To address this issue, SAMP8 were exposed for 4 weeks to the CMS paradigm and treated with RL-118, an 11β-HSD1 inhibitor. In fact, several pieces of evidence link CMS exposure to reduced cognitive performance, while inhibition of 11β-HSD1 has been associated with reduction of GC activity and cognitive improvement. The aim of this project was to assess whether RL-118 treatment could restore the deleterious effects of CMS on cognition and behavioural abilities, but also on molecular mechanisms that compromise healthy ageing in SAMP8 mice. On the one hand, we determined the target engagement between RL-118 and 11β-HSD1. Therefore all the beneficial effects previously described in SAMP8 treated with the drug can undoubtedly be attributed to the inhibition of this enzyme. Besides, herein we observed decreased DNA methylation, hydroxymethylation and histone phosphorylation induced by CMS but, on the contrary, increased after RL-118 treatment. In addition, CMS exposure produced ROS damage accumulation, and increments of pro-oxidant enzymes as well as pro-inflammatory mediators through NF-κB pathway and astrogliosis markers, like Gfap. Of note, those modifications were recovered by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signalling, autophagy was increased in SAMP8 treated with RL-118 mice. Also, we found that amyloidogenic APP processing pathway was favoured and decreased synaptic plasticity and neuronal remodelling markers in mice under CMS, but changed after RL-118 treatment. In consequence, detrimental effects on behaviour and cognitive performance were detected in CMS exposed mice, although recovered after concomitant 11β-HSD1 inhibition by RL-118. Overall, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence. However and most important, 11β-HSD1 inhibition through RL-118 turned up to restore the majority of these detrimental effects caused by CMS, indicating that GC excess attenuation may become a potential therapeutic strategy for age-related cognitive decline and AD.

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Targeting Synaptic Plasticity in Experimental Models of Alzheimer’s Disease

Cited by 87 publications

References 94 publications

The Role of Kv7 Channels in Neural Plasticity and Behavior

The Role of Kv7 Channels in Neural Plasticity and Behavior

Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the β-Amyloidopathy Model in vitro

RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis

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