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Prodromal stages of neurodegenerative diseases: proposals for new approaches in diagnosis and intervention.
Full text linkAs life expectancy is increasing, new ways to maintain a good quality of life and to prevent neurodegenerative diseases are fundamental.
In Study 1, we aimed at investigating both behavioral and neurofunctional effects of a 5-weeks treatment for patients with single and multiple-domain aMCI. There is evidence that non-specific domain trainings might be beneficial for patients with MCI, and a non-invasive modulation technique, Prismatic Adaptation (PA), seems to entail a diffuse effect on higher cognition as well. Thus, we implemented a digital treatment involving the use of PA combined with Serious Games. To date, we have recruited 10 patients, who underwent neuropsychological assessments and resting-state fMRI exams, before and after the treatment. They were divided into two groups, one who received PA with real lenses (experimental), and the other who received PA with neutral lenses (control). Our results suggest that the 5-weeks treatment was beneficial in preventing cognitive deterioration in that timeframe, and in sustaining attention, in both groups. We also observed an increased anti-correlation between the Default Mode Network (DMN) and the Dorsal Attention Network (DAN) during resting-state in the experimental group after the treatment. This result is in line with current literature, and it also reflects the potential neurofunctional effects of PA.
Study 2.1 and 2.2 focus on the attention capabilities of healthy elderlies and their differences from aMCI patients. In Study 2.1 we explored the characteristics of attentional subcomponents, namely alerting, orienting, and executive control, in healthy individuals older than 65 years old, and investigated whether PA could modulate them. To do so, we recruited 20 participants and administered them with the Attention Network Test (ANT) before and after one single session of PA. Results suggest that only the alerting component was modulated by PA. In Study 2.2 we compared the performances at ANT of the healthy participants matched with the aMCI patients of Study 1. We found patients being significantly more slowly and less accurate than healthy elderlies.
Finally, the Study 3 presents a single case of unilateral right tactile agnosia, in the context of a rare neurodegenerative disease, namely Cortical Basal Syndrome (CBS). The patient, a 55-year-old woman, initially presented with a left frontoparietal atrophy and the outcome of the surgical removal of a right parietal oligodendroglioma. She referred difficulties in haptic object recognition and in right-hand sensitivity. We performed an experimental evaluation of somatosensory functions and tactile agnosia, targeting every level of tactile processing. We recruited 18 healthy controls age- and education-matched. Furthermore, we followed the patient’s clinical evolution for three years. The initial neuropsychological assessment revealed only apraxia for the right hand. The patient showed normal tactile sensitivity and she was accurate for most hylognosis functions. Conversely, she was impaired with the right hand in meaningless-shapes test. Three years after symptoms onset, a DaTSCAN, previously negative, became positive. The MR showed a progression of the left frontoparietal atrophy in the absence of a tumoral relapse. Behaviourally, apraxia and morphoagnosia appeared also in the left hand. The patient's clinical profile is consistent with the diagnosis of CBS and unilateral tactile agnosia as the primary symptom onset. This is the third case described in the literature manifesting morphoagnosia without hyloagnosia and the first description of such dissociation in a case with CBS.
Overall, our studies demonstrate that the understanding of physiological changes in the elderly needs further exploration. Such knowledge can be indispensable for early diagnoses and for the development of treatments, both in the context of most common conditions, e.g., MCI, and even in rare neurodegenerative diseases, e.g., CBS
Role of microglia and astrocytes in inflammatory processes involving neurological diseases, chronic pain, and psychiatric disorders, with emphasis on the purinergic P2X7 receptor
Full text linkUnder pathological conditions microglia (resident central nervous system (CNS) immune cells) become activated, and produce reactive oxygen and nitrogen species and pro-inflammatory cytokines: molecules that can contribute to disorders including stroke, traumatic brain injury, progressive neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and several retinal diseases. Given that ATP is frequently released from CNS neurons during tissue damage and inflammation, its actions on microglia-mediated toxicity are especially pertinent. For example, the ATP-gated P2X7 purinergic receptor (P2X7R) cation channel is up-regulated around amyloid beta-peptide plaques in transgenic mouse models of Alzheimer's disease and co-localizes to microglia and astrocytes. Upregulation of P2X7R on microglia occurs also following spinal cord injury and after brain ischemia. ATP, via activation of P2X7R, is one of the most powerful stimuli for secretion of the key pro-inflammatory cytokine interleukin-1β (IL-1β) in its mature form. This project investigates the pharmacological and biochemical behaviors of P2X7R on microglia and astrocytes cultured from rat cerebral cortex, spinal cord and cerebellum, and the relationship between these two glial cell types.
ATP is an efficient stimulus for IL-1β secretion only after the cells have undergone a short 'priming' with endotoxin (lipopolysaccharide (LPS)). Indeed LPS, but not ATP caused release of IL-1β from cortical microglia. However, it is known that the greater part of the IL-1β thus released is the precursor (biologically inactive) form. Purified (>99%) cortical microglia and enriched (>95%) astrocytes were primed for 2 hours with LPS, followed by addition of ATP for 1 hour. Culture medium was then collected and the content of IL-1β quantified by ELISA. The effects of LPS and ATP were concentration-dependent; although LPS alone (but not ATP) modestly stimulated IL-1β release, levels of cytokine release were much higher from primed cells incubated with ATP. The ATP-dependent component was fully blocked by selective P2X7R antagonists, and followed their known rank order of target potency. The P2X7R priming response was also seen with spinal cord and cerebellar microglia, a finding not described in the literature until now.
To rule out a contribution by the minor population of microglia in our astrocyte cultures, the latter were treated with the lysosomotropic agent L-leucyl-L-leucine methyl ester (L-LME) which selectively eliminates cells with cytotoxic potential (e.g. macrophages, microglia). Immunocytochemical and molecular biological evaluation showed L-LME-treated cortical and spinal cord astrocytes to be fully depleted of microglia. These purified astrocytes failed to respond to LPS, and did not show the ATP priming behavior. Responsiveness was recovered upon addition of microglia to the L-LME-treated astrocytes and, moreover, a far more robust release of IL-1β occurred than that achieved with the same numbers of microglia alone. This astrocyte-microglia interaction was also observed for LPS-stimulated release of nitric oxide and IL-6, and was not mediated by astrocyte-derived soluble factors.
Lastly, the LPS/ATP priming behavior was studied by examining the ability of other agents, linked to neuropathology, to replace either LPS or ATP. Neither ethanol (ethanol intoxication; in place of LPS) nor amyloid beta-peptides (Alzheimer disease; in place of ATP) were able to provoke IL-1β release from microglia. However, both zymosan and poly(I:C), agonists of Toll-like receptors -2 and -3, respectively, were capable of substituting LPS (a Toll-like receptor 4 agonist) in the P2X7R priming response. Release of IL-1β in all these cases was antagonized by inhibitors of p38 mitogen-activated protein kinase (a stress response kinase).
TLRs contribute to CNS immunocompetent cell activation and the resulting pro-inflammatory cascade producing pathological pain. TLR4 recognizes not only LPS, but also ligands called damage associated molecular patterns, released by the injured tissue The involvement of extracellular TLR4 and TLR2, as well as TLR3 in preclinical pain models has been demonstrated. The findings described here further support the notion of astrocyte/microglia interaction, which may improve our understanding in how these cells respond to CNS injury or inflammation, in particular where TLRs are involve
Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: a review.
No full textCells of the immune system and the central nervous system are capable of interacting with each other. The former cell populations respond to infection, tissue injury and trauma by releasing substances capable of provoking an inflammatory reaction. Inflammation is now recognized as a key feature in nervous system pathologies such as chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders such as anxiety/depression and schizophrenia. Neuroinflammation may also raise the brain's sensitivity to stress, thereby effecting stress-related neuropsychiatric disorders like anxiety or depression. The cytokine network plays a large part in how immune system cells influence the central nervous system. Further, inflammation resulting from activation of innate immune system cells in the periphery can impact on central nervous system behaviors, such as depression and cognitive performance. In this review, we will present the reader with the current state of knowledge which implicates both microglia and mast cells, two of the principle innate immune cell populations, in neuroinflammation. Further, we shall make the case that dysregulation of microglia and mast cells may impact cognitive performance and, even more importantly, how their cell-cell interactions can work to not only promote but also amplify neuroinflammation. Finally, we will use this information to provide a starting point to propose therapeutic approaches based upon naturally-occurring lipid signaling molecules
Intracellular Ion Channel CLIC1: Involvement In Microglia-Mediated ß-Amyloid Peptide(1-42) Neurotoxicity
No full textMicroglia can exacerbate central nervous system disorders, including stroke and chronic progressive neurodegenerative diseases such as Alzheimer disease. Mounting evidence points to ion channels expressed by microglia as contributing to these neuropathologies. The Chloride Intracellular Channel (CLIC) family represents a class of chloride intracellular channel proteins, most of which are localized to intracellular membranes. CLICs are unusual in that they possess both soluble and integral membrane forms. Amyloid beta-peptide (A beta) accumulation in plaques is a hallmark of familial Alzheimer disease. The truncated A beta(25-35) species was shown previously to increase the expression of CLIC1 chloride conductance in cortical microglia and to provoke microglial neurotoxicity. However, the highly pathogenic and fibrillogenic full-length A beta(1-42) species was not examined, nor was the potential role of CLIC1 in mediating microglial activation and neurotoxicity by other stimuli (e.g. ligands for the Toll-like receptors). In the present study, we utilized a two chamber Transwell (TM) cell culture system to allow separate treatment of microglia and neurons while examining the effect of pharmacological blockade of CLIC1 in protecting cortical neurons from toxicity caused by A beta(1-42)- and lipopolysaccaride-stimulated microglia. Presentation of A beta(1-42) to the upper, microglia-containing chamber resulted in a progressive loss of neurons over 3 days. Neuronal cell injury was prevented by the CLIC1 ion channel blockers IAA-94 [(R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] and niflumic acid (2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid) when presented to the upper chamber only. Incubation of microglia with lipopolysaccharide plus interferon-gamma led to neuronal cell injury which, however, was insensitive to inhibition by the CLIC1 channel blockers, suggesting a degree of selectivity in agents leading to CLIC1 activation
Corrigendum: An Inflammation-Centric View of Neurological Disease: Beyond the Neuron
Full text linkIn the original article, there was a mistake in the legend for Figure 1 as published. We neglected to include the citation for the figure from which our figure was adapted and modified. The correct figure legend appears below. Figure 1. Microglia, like Janus, the two-faced Roman god of beginnings and transitions, display two sides—physiological as well as pathological. While microglial cell activation participates in surveillance that functions to maintain homeostasis and promote synaptic maturation, prolonged exposure to pathogen activators or in settings of systemic inflammation, asmay occur in conditions such as diabetes or obesity, can culminate in a state of chronic, non-resolving neuroinflammation. Ultimately, these responses will provoke functional and structural changes and neuronal cell death (neurodegeneration). [Adapted and modified from Heneka et al. (2015). Neuroinflammation in Alzheimer’s disease (Figure 1)]. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated
Mast cells, glia and neuroinflammation: partners in crime?
Full text linkGlia and microglia in particular elaborate pro-inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro-inflammatory signals released from other non-neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood-spinal cord and blood-brain barriers when barrier compromise results from CNS pathology. Growing evidence of mast cell-glia communication opens new perspectives for the development of therapies targeting neuroinflammation by differentially modulating activation of non-neuronal cells that normally control neuronal sensitization - both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be up-regulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamine family. One such member, N-palmitoylethanolamine is proposed to have a key role in maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N-Palmitoylethanolamine has proven efficacious in mast-cell-mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell-microglia cross-talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings
Microglia and mast cells: two tracks on the road to neuroinflammation.
No full textOne of the more important recent advances in neuroscience research is the understanding that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. The emerging realization is that glia and microglia, in particular, (which are the brain's resident macrophages), constitute an important source of inflammatory mediators and may have fundamental roles in CNS disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin. Mast cells are of particular relevance in this context. These immunity-related cells, while resident in the CNS, are capable of migrating across the blood-spinal cord and blood-brain barriers in situations where the barrier is compromised as a result of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communications and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization, both peripherally and centrally. This review aims to provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells, in particular, and the possibility that mast cell-microglia crosstalk may contribute to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerate disease progression, as well as promote pain transmission pathways. We conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signaling pathways from the periphery to the brain in such settings.-Skaper, S. D., Giusti, P., Facci, L. Microglia and mast cells: two tracks on the road to neuroinflammation
Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator.
No full textGlia are key players in a number of nervous system disorders. Besides releasing glial and neuronal signaling molecules directed to cellular homeostasis, glia respond also to pro-inflammatory signals released from immune-related cells, with the mast cell being of particular interest. A proposed mast cell-glia communication may open new perspectives for designing therapies to target neuroinflammation by differentially modulating activation of non-neuronal cells normally controlling neuronal sensitization-both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be upregulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamines, whose principal family members are the endocannabinoid N-arachidonoylethanolamine (anandamide), and its congeners N-stearoylethanolamine, N-oleoylethanolamine, and N-palmitoylethanolamine (PEA). A key role of PEA may be to maintain cellular homeostasis when faced with external stressors provoking, for example, inflammation: PEA is produced and hydrolyzed by microglia, it downmodulates mast cell activation, it increases in glutamate-treated neocortical neurons ex vivo and in injured cortex, and PEA levels increase in the spinal cord of mice with chronic relapsing experimental allergic encephalomyelitis. Applied exogenously, PEA has proven efficacious in mast cell-mediated experimental models of acute and neurogenic inflammation. This fatty acid amide possesses also neuroprotective effects, for example, in a model of spinal cord trauma, in a delayed post-glutamate paradigm of excitotoxic death, and against amyloid β-peptide-induced learning and memory impairment in mice. These actions may be mediated by PEA acting through "receptor pleiotropism," i.e., both direct and indirect interactions of PEA with different receptor targets, e.g., cannabinoid CB2 and peroxisome proliferator-activated receptor-alpha
Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons
Full text linkThe perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions
Synaptic Plasticity, Dementia and Alzheimer Disease
No full textNeuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparent that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid b-peptide (Ab) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Ab, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Ab oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts undergo dynamic changes in number, size and shape in response to variations in hormonal status, developmental stage, and changes in afferent input. It is perhaps not unexpected that loss of spine density may be linked to cognitive and memory impairment in AD, although the underlying mechanism(s) remain uncertain. This article aims to present a critical overview of current knowledge on the bases of synaptic dysfunction in neurodegenerative diseases, with a focus on AD, and will cover amyloid- and non-amyloid-driven mechanisms. We will consider also emerging data dealing with potential therapeutic approaches for ameliorating the cognitive and memory deficits associated with these disorders
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