1,721,065 research outputs found
Glial dysfunction in the pathogenesis of neuropsychiatric disorders: beyond inflammation, toward the development of novel therapies
No full textAlzheimer's disease (AD) is the most common late-onset, progressive, and age-dependent neurodegenerative disorder associated with dementia (Brookmeyer R., 2007). Deposit of β-amyloid (Aβ) and accumulation of hyperphosphorylated τ protein filaments in neurofibrillary tangles (NFTs) are considered peculiar hallmarks of AD (Ramirez-Bermudez J., 2012).
Several studies shown that excess amount of Aβ causes neuronal multiple cytotoxic mechanisms, including increase of the intracellular Ca2+ level, oxidative stress, receptor-mediated activation of cell-death cascades, astrocyte activation, and Wnt pathway deregulation (Selkoe D.J. et al., 2008).
It has been demonstrated that the neurotrophin S100B, whose levels correlate with the degree of astrocyte activation, is able to disrupt the Wnt pathway through the involvement of Dickopff-1 (Dkk-1) (Esposito G. et al., 2008). In addition, it has been suggested that dysfunction of Wnt pathway could contribute to AD pathology (Inestrosa N.C. et al., 2010).
On the basis of these consideration, pharmacological manipulation of the Wnt cascade could be useful to achieve neuroprotection, also in AD. In this context, palmitoylethanolamide (PEA), an endogenous lipid compound, could be a promising agent. Indeed, it has been already demonstrated that this compound exerts marked antinflammatory actions and it is able to counteract astrocyte activation (Scuderi C. et al., 2011). PEA is the amide of ethanolamine and palmitic acid, abundant in the central nervous system and produced by glial cells (Cadas H. et al., 1996). PEA's beneficial properties seems to depend on the activation of the peroxisome proliferator-activated receptor-alpha (PPAR-α) (Scuderi C. et al., 2012; D'Agostino G. et al., 2012).
Here we describe the neuroprotective effects of systemic administration of PEA in adult male rats given intrahippocampal injection of Aβ(1-42). In order to investigate the molecular mechanisms responsible for the effects induced by PEA, we co-administered PEA with the GW6471, an antagonist of peroxisome proliferator-activated receptor-α (PPAR-α). Making use of the western blot and immunofluorescence techniques, we found that Aβ(1-42) injection results in severe changes of Wnt pathway. Interestingly PEA was able to restore the Aβ-induced alterations through PPAR-α involvement.
Considering the extreme safety and tolerability of PEA, already proven in humans, these findings offer new opportunities in the development of innovative AD treatment
How useful are biomarkers for the diagnosis of Alzheimer’s disease and especially for its therapy?
No full textAlzheimer’s disease (AD) is a slowly progressive neurodegenerative disease with no available effective treatment. It is possible to distinguish an early-onset AD that affects a limited number of subjects of young age, and a sporadic or late-onset form of the disease
that affects the vast majority of subjects who are diagnosed with AD. As life expectancy has increased considerably over the past century, the number of people diagnosed with AD has grown exponentially. So, AD and AD-related pathologies represent a huge social and economic burden. The number of individuals waiting for effective disease-modifying therapy is impressive. It is estimated that 50
million people worldwide live with dementia, the majority of these cases are caused by AD (World Health Organization, 2021). In the
US about 6 million individuals are living with AD, and more than 9 million people are in EU member states (OECD and European Union,
2020). The costs of health care and long-term care are substantial. Given this massive societal impact, enormous efforts have been made to understand the pathogenetic mechanisms of the disease with the hope of identifying new targets and, therefore, developing effective drugs. However, despite huge preclinical and clinical scientific efforts, therapeutic advances are truly modest, and the clinical practice is still anchored to the use of drugs modulating the cholinergic and glutamatergic systems
Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic
Full text linkCOVID-19, initially regarded as specific lung disease, exhibits an extremely broad spectrum of symptoms. Extrapulmonary manifestations of the disease also include important neuropsychiatric symptoms with atypical characteristics. Are these disturbances linked to stress accompanying every systemic infection, or are due to specific neurobiological changes associated with COVID-19? Evidence accumulated so far indicates that the pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism or in response to cytokine storm), all affecting the brain. It is reasonable to hypothesize that all these events may initiate or worsen psychiatric and cognitive disorders. Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by astrocytes which are the homeostatic cell par excellence. Astrocytes undergo complex morphological, biochemical, and functional remodeling aimed at mobilizing the regenerative potential of the central nervous system. If the brain is not directly damaged, resolution of systemic pathology usually results in restoration of the physiological homeostatic status of neuroglial cells. The completeness and dynamics of this process in pathological conditions remain largely unknown. In a subset of patients, glial cells could fail to recover after infection thus promoting the onset and progression of COVID-19-related neuropsychiatric diseases. There is evidence from post-mortem examinations of the brains of COVID-19 patients of alterations in both astrocytes and microglia. In conclusion, COVID-19 activates a huge reactive response of glial cells, that physiologically act as the main controller of the inflammatory, protective and regenerative events. However, in some patients the restoration of glial physiological state does not occur, thus compromising glial function and ultimately resulting in homeostatic failure underlying a set of specific neuropsychiatric symptoms related to COVID-19
La neuroinfiammazione nel morbo di Alzheimer come target per nuove strategie terapeutiche.
No full textNeuroglial Roots of Neurodegenerative Diseases: Therapeutic Potential of Palmitoylethanolamide in Models of Alzheimer's Disease
No full textThe growth of knowledge about the molecular mechanisms underlying Alzheimer's disease (AD) has highlighted the role of neuroinflammation in the pathophysiology of this disorder. AD is classically characterized by the deposit of misfolded proteins: the extracellular accumulation of beta amyloid peptide (A beta), and the formation of intracellular neurofibrillary tangles. However, it is clear that many other cellular dysfunctions occur. Among these, a prominent role is exerted by the inflammatory process which is a consequence of the over-activation of glial cells. Indeed, several models of AD have demonstrated that glia modify their functions, losing the physiological supportive role. These cells instead acquire a pro-inflammatory phenotype, thus contributing to exacerbate A beta toxicity. The relationship between neurodegeneration and neuroinflammation is strictly interdependent, and research efforts are now addressed to antagonize both processes simultaneously. Along this line palmitoylethanolamide (PEA) has attracted much attention because of its numerous pharmacological properties, particularly those related to the modulation of peripheral inflammation through the peroxisome proliferator activated receptor-involvement. In light of these considerations, we explored the anti-inflammatory and neuroprotective effects of PEA in rat neuronal cultures and organotypic hippocampal slices challenged with A beta, and treated with PEA in the presence or absence of a selective peroxisome proliferator activated receptor-alpha antagonist. The data indicate that PEA is able to blunt A beta-induced astrocyte activation and to exert a marked protective effect on neurons. These findings highlight new pharmacological properties of PEA and suggest that this compound may provide an effective strategy for AD
Antinflammatory/neuroprotective properties of palmitoylethanolamide in a model of Alzheimer’s disease
No full textPALMITOYLETHANOLAMIDE ATTENUATES ASTROCYTE ACTIVATION AND NEUROINFLAMMATION IN AN ANIMAL MODEL OF ALZHEIMER'S DISEASE
No full textRole of astrocytes in major neurological disorders: The evidence and implications
No full textGiven the huge amount and great complexity of astrocyte functions in the maintenance of brain homeostasis, it is easily understood how alterations in their physiology may be involved in the pathogenesis of many, if not all, neurological disorders. This assumption is strongly supported by accumulated evidence produced in humans and in experimental models of pathology. Based on these considerations, it is reasonable to encourage studies aimed at improving the knowledge about the implicated mechanisms, and astroglial cells can be considered as the innovative target for new, and possibly more effective, drug therapies. (c) 2013 IUBMB Life, 65(12):957-961, 2013
Targeting neuroinflammation in Alzheimer’s disease
Full text linkAlmost 47 million people suffer from dementia worldwide, with an estimated
new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately
60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the
greatest global public health challenges. Currently used drugs alleviate the symptoms of AD
but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to
find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest
therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and
tau tangles, new therapeutic approaches have other targets. One of the newest and most promising
strategies is the control of reactive gliosis, a multicellular response to brain injury. This
phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular
dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in
the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and
tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a
proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore
their physiological functions and control the neuroinflammatory process offer new therapeutic
opportunities for this devastating disease. In this review, we describe the role of neuroinflammation
in the AD pathogenesis and progression and then provide an overview of the recent
research with the aim of developing new therapies to treat this disorder
Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARγ involvement
No full textThe amyloidogenic cascade is regarded as a key factor at the basis of Alzheimer's disease (AD) pathogenesis. The aberrant cleavage of amyloid precursor protein (APP) induces an increased production and a subsequent aggregation of beta amyloid (Aβ) peptide in limbic and association cortices. As a result, altered neuronal homeostasis and oxidative injury provoke tangle formation with consequent neuronal loss. Cannabidiol (CBD), a Cannabis derivative devoid of psychotropic effects, has attracted much attention because it may beneficially interfere with several Aβ-triggered neurodegenerative pathways, even though the mechanism responsible for such actions remains unknown. In the present research, the role of CBD was investigated as a possible modulating compound of APP processing in SHSY5YAPP+ neurons. In addition, the putative involvement of peroxisome proliferator-activated receptor-γ (PPARγ) was explored as a candidate molecular site responsible for CBD actions. Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5YAPP+ with the consequent decrease in Aβ production. Moreover, CBD promoted an increased survival of SHSY5Y APP+ neurons, by reducing their long-term apoptotic rate. Obtained results also showed that all, here observed, CBD effects were dependent on the selective activation of PPARγ. Copyright © 2013 John Wiley & Sons, Ltd
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