The role of glial cells in mental illness: a systematic review on astroglia and microglia as potential players in schizophrenia and its cognitive and emotional aspects

Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including delusions, hallucinations, disorganized speech and behavior, and cognitive impairment. Recent research has suggested that the immune system dysregulation may play a significant role in the pathogenesis of schizophrenia, and glial cells, such as astroglia and microglia known to be involved in neuroinflammation and immune regulation, have emerged as potential players in this process. The aim of this systematic review is to summarize the glial hallmarks of schizophrenia, choosing as cellular candidate the astroglia and microglia, and focusing also on disease-associated psychological (cognitive and emotional) changes. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Scopus, and Web of Science for articles that investigated the differences in astroglia and microglia in patients with schizophrenia, published in the last 5 years. The present systematic review indicates that changes in the density, morphology, and functioning of astroglia and microglia may be involved in the development of schizophrenia. The glial alterations may contribute to the pathogenesis of schizophrenia by dysregulating neurotransmission and immune responses, worsening cognitive capabilities. The complex interplay of astroglial and microglial activation, genetic/epigenetic variations, and cognitive assessments underscores the intricate relationship between biological mechanisms, symptomatology, and cognitive functioning in schizophrenia

Physical Exercise as Disease-Modifying Alternative against Alzheimer’s Disease: A Gut–Muscle–Brain Partnership

Alzheimer’s disease (AD) is a common cause of dementia characterized by neurodegenerative dysregulations, cognitive impairments, and neuropsychiatric symptoms. Physical exercise (PE) has emerged as a powerful tool for reducing chronic inflammation, improving overall health, and preventing cognitive decline. The connection between the immune system, gut microbiota (GM), and neuroinflammation highlights the role of the gut–brain axis in maintaining brain health and preventing neurodegenerative diseases. Neglected so far, PE has beneficial effects on microbial composition and diversity, thus providing the potential to alleviate neurological symptoms. There is bidirectional communication between the gut and muscle, with GM diversity modulation and short-chain fatty acid (SCFA) production affecting muscle metabolism and preservation, and muscle activity/exercise in turn inducing significant changes in GM composition, functionality, diversity, and SCFA production. This gut–muscle and muscle–gut interplay can then modulate cognition. For instance, irisin, an exercise-induced myokine, promotes neuroplasticity and cognitive function through BDNF signaling. Irisin and muscle-generated BDNF may mediate the positive effects of physical activity against some aspects of AD pathophysiology through the interaction of exercise with the gut microbial ecosystem, neural plasticity, anti-inflammatory signaling pathways, and neurogenesis. Understanding gut–muscle–brain interconnections hold promise for developing strategies to promote brain health, fight age-associated cognitive decline, and improve muscle health and longevity

Alzheimer's disease and depression in the elderly: A trajectory linking gut microbiota and serotonin signaling

: The occurrence of neuropsychiatric symptoms in the elderly is viewed as an early sign of subsequent cognitive deterioration and conversion from mild cognitive impairment to Alzheimer's disease. The prognosis in terms of both the severity and progression of clinical dementia is generally aggravated by the comorbidity of neuropsychiatric symptoms and decline in cognitive function. Undeniably, aging and in particular unhealthy aging, is a silent "engine of neuropathology" over which multiple changes take place, including drastic alterations of the gut microbial ecosystem. This narrative review evaluates the role of gut microbiota changes as a possible unifying concept through which the comorbidity of neuropsychiatric symptoms and Alzheimer's disease can be considered. However, since the heterogeneity of neuropsychiatric symptoms, it is improbable to describe the same type of alterations in the bacteria population observed in patients with Alzheimer's disease, as well as it is improbable that the variety of drugs used to treat neuropsychiatric symptoms might produce changes in gut bacterial diversity similar to that observed in the pathophysiology of Alzheimer's disease. Depression seems to be another very intriguing exception, as it is one of the most frequent neuropsychiatric symptoms in dementia and a mood disorder frequently associated with brain aging. Antidepressants (i.e., serotonin reuptake inhibitors) or tryptophan dietary supplementation have been shown to reduce Amyloid β-loading, reinstate microbial diversity and reduce the abundance of bacterial taxa dominant in depression and Alzheimer's disease. This review briefly examines this trajectory by discussing the dysfunction of gut microbiota composition, selected bacterial taxa, and alteration of tryptophan and serotonin metabolism/neurotransmission as overlapping in-common mechanisms involved with depression, Alzheimer's disease, and unhealthy aging

n-3 PUFA improves psychological well-being during menopausal transition

Females show an increased risk of cognitive impairment when approaching menopause because of the loss of ovarian function and estrogen deficiency occurring during the climacteric. In addition, menopause is closely associated with emotional disorders, such as anxiety and depression. Data on risk and protection factors have yielded robust evidence on the effects of lifestyle factors, such as diet, in preserving emotional and cognitive functioning. The impact of specific lifestyle factors on psychological health indicates that there may be potential to improve (or at least stabilise) declining trajectories of emotional and cognitive functions in menopause. This work focused on the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) supplementation on cognitive functions, depression and anxiety during the menopausal transition. This systematic review, performed according to PRISMA guidelines, considered all articles published until December 31st 2021 and the search was performed on two databases, PUBMED and SCOPUS. The fields of interest were “menopausal transition”, “n-3 PUFA” and “cognitive and affective aspects”. Out of the 361 articles found on PUBMED and 283 on Scopus, 17 met the inclusion criteria. They encompassed 11 human and 6 experimental studies. Most clinical and preclinical studies report relieved depressive symptoms in relation to n-3 PUFA intake in menopause. Controversial results have been found in menopausal women on anxiety and cognitive functions, while in the few studies carried out in animal models n-3 PUFA reduced anxiety symptoms and improved cognitive functions. Taken together, the current results show beneficial effects of n-3 PUFA on emotional and cognitive behaviours during menopause transition. However, further investigations should be performed to increase knowledge about the real effectiveness of n-3 PUFA on psychological well-being in this delicate period of feminine life

Behavioral effects of long-term administration of palmitoylethanolamide on Tg2576 mice

Aim: To date, pharmacological approaches to treat dementia and particularly Alzheimer disease (AD) remain uncertain and unclear. In this context, palmitoylethanolamide (PEA) has been emerging as an important analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in both central and peripheral nervous systems as well as immune cells, and has demonstrated high safety and tolerability. PEA is present in certain foods we use every day such as egg yolk, corn, peanut and soy oils and is also produced by many cells in our organism. It can be found in high concentrations in brain tissues and is synthesized starting by lipid components of the cellular membranes. In the present study, we sought to investigate the behavioral modifications potentially induced by a chronic administration of ultra-micronized PEA (i.e., a micrometer-sized crystalline form that improves both its pharmacokinetics and bioavailability) for 6-months in transgenic mice expressing mutant APP (Tg2576 mice). These mice express high levels of mutated human APP and with advancing age develop both amyloid peptide accumulation and amyloid plaques in the brain, as well as behavioral and cognitive deficits; thus, they represent a widely accepted animal model of AD. Methods: The 6-month administration of PEA in Tg2576 mice and the wild-type (WT) control group was via a subcutaneous (s.c.) delivery system. Mice were subjected to s.c. implantation of PEA or placebo pellets at 6 months of age. PEA effects on motor, cognitive and emotional performances were monitored longitudinally, by a battery of behavioral tasks, within three different ages, corresponding to a pre-symptomatic phase (T0 = 3 months), a mild-symptomatic phase (T1 = 6.5 months) and a fully symptomatic phase (T2 = 11-12 months; ie., at the end of the chronic supplementation). All mice underwent the behavioral assessment by using the following battery of validated tests: Elevated Plus Maze (EPM), to assess anxiety levels and locomotor skills; Rotarod Test (RT), to assess motor coordination skills; Y-Maze Spontaneous Alternation Test (Y-Maze), to assess working memory skills; Novel Object Recognition Test (NORT), to assess mnestic and discriminative skills; Tail Suspension Test (TST), to assess depressive behaviors. Results: Behavioral analyses performed on our mice demonstrate that chronic PEA supplementation exerts beneficial effects on NORT mnesic performances of Tg2576 mice at T2. Specifically, in Tg2576 mice chronic PEA supplementation restored the novelty recognition memory impaired during the fully symptomatic phase, while did not affect working memory, motor coordination, anxiety, and depressive-like alterations. No PEA effects were observed in WT mice. Conclusions: PEA is able to counteract specific hippocampal-dependent mnesic deficits typical of AD. Our data suggest the likely therapeutic potential of ultra-micronized PEA as an early treatment in AD. These findings should be further investigated to increase knowledge of the effects of PEA as a safe and low-cost nutraceutical tool useful to improve quality of life in AD

Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer’s Disease Animal Models of Lipopolysaccharide-Induced Inflammation

Alzheimer’s disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation

n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review

Women show an increased risk of cognitive impairment and emotional disorders, such as anxiety and depression, when approaching menopause. Data on risk and protection factors have yielded robust evidence on the effects of lifestyle factors, such as diet, in preserving emotional and cognitive functioning. This review focused on the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on anxiety, depression, and cognition during the menopausal transition. This systematic review considered all articles published until 31 December 2021, and the search was performed on two databases, PubMed and Scopus. The fields of interest were “menopause”, “n-3 PUFA” and “emotional and cognitive aspects”. Out of the 361 articles found on PubMed and 283 on Scopus, 17 met inclusion criteria. They encompassed 11 human and 6 animal studies. Most studies reported relieved depressive symptoms in relation to n-3 PUFA intake. While controversial results were found on anxiety and cognition in humans, n-3 PUFA consistently reduced anxiety symptoms and improved cognition in animal studies. Taken together, n-3 PUFA intake shows beneficial effects on emotional and cognitive behaviours during menopause transition. However, further investigations could increase knowledge about the effectiveness of n-3 PUFA on psychological well-being in this delicate period of feminine life

Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview

Neuroinflammation is a pathophysiological condition associated with damage to the nervous system. Maternal immune activation and early immune activation have adverse effects on the development of the nervous system and cognitive functions. Neuroinflammation during adulthood leads to neurodegenerative diseases. Lipopolysaccharide (LPS) is used in preclinical research to mimic neurotoxic effects leading to systemic inflammation. Environmental enrichment (EE) has been reported to cause a wide range of beneficial changes in the brain. Based on the above, the purpose of the present review is to describe the effects of exposure to EE paradigms in counteracting LPS-induced neuroinflammation throughout the lifespan. Up to October 2022, a methodical search of studies in the literature, using the PubMed and Scopus databases, was performed, focusing on exposure to LPS, as an inflammatory mediator, and to EE paradigms in preclinical murine models. On the basis of the inclusion criteria, 22 articles were considered and analyzed in the present review. EE exerts sex- and age-dependent neuroprotective and therapeutic effects in animals exposed to the neurotoxic action of LPS. EE’s beneficial effects are present throughout the various ages of life. A healthy lifestyle and stimulating environments are essential to counteract the damages induced by neurotoxic exposure to LPS

Chronic administration of palmitoylethanolamide counteracts cognitive decline in Tg2576 Mice

Palmitoylethanolamide (PEA) has been emerging as a safe and well tolerated analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in the nervous system. PEA is present in foods, as egg yolk, corn, peanut and soy oil. It is synthesized from lipid components of cellular membranes and can be found in high concentrations in brain tissues. In this study, we evaluated the effects of a chronic (6 months) administration of ultra-micronized PEA on cognitive decline in transgenic Tg2576 (Tg) mice expressing mutant APP. When aged, Tg mice develop accumulation of amyloid peptide and amyloid plaques in the brain, as well as cognitive deficits, representing thus an animal model of AD. PEA administration was performed via a subcutaneous delivery system in Tg mice and wild-type control group (from 6 to 12 months of age). PEA effects on behavior were observed longitudinally in a pre-symptomatic phase (3 months), a mild-symptomatic phase (6.5 months) and a full-symptomatic phase (11-12 months). Behavioral assessment was performed by using the following validated tests: Elevated Plus Maze, Rotarod Test, Y-Maze Spontaneous Alternation Test, Novel Object Recognition Test, Tail Suspension Test and Morris Water Maze. PEA administration restored the novelty recognition memory of Tg mice during the full-symptomatic phase. PEA was able to counteract hippocampal- dependent mnesic deficits, suggesting the therapeutic potential for the early treatment of AD. Further in progress analyses involve histological evaluation of dendritic branching, spine number, amyloid plaques and glial reactivity in the hippocampal CA1. This research is aimed to increase knowledge of the effects of PEA as a safe and low-cost nutraceutical tool useful to improve quality of life in AD

Specialized pro-resolving mediator RvD1 reduces neuroinflammation in a transgenic rat model of Parkinson’s disease

The neuroinflammatory processes in Parkinson’s disease (PD) are usually associated with activation of the immune system caused by a growing aggregation of α-synuclein (α-Syn) in central nervous system. The active immune response in brain of PD patients leads to infiltration of lymphocytes, production of cytokines and microgliosis, these features could be a consequence of failure to resolve inflammation, a process mediated by a superfamily of endogenous lipids termed specialized pro-resolvin mediators (SPMs). A previous study from our group has shown that precocious treatment with resolvin D1 (RvD1) prevents the onset of PD by attenuating immune response in a rat model of PD. Herein, we explored the long-term effect of RvD1 in α-Syn rats by treating them with intraperitoneal injections twice a week, starting at early stage of the disease (2 months old) until the symptomatic phase (12 months old). Hence, we assessed motor deficit evaluated through Rotarod test and the infiltration of the main CD45+ leukocyte cell populations (i.e. CD3+ T-cells, CD45RA+ B-cells, CD161+ NK-cells and CD45/CD11bhigh macrophages) within substantia nigra and striatum by flow cytometry. We found that α-Syn rats showed a higher degree of nigral and striatal infiltration of all cell subsets compared to age-matched wildtype rats and that RvD1 treatment not only ameliorated motor deficits but also reduced their infiltration in both anatomical regions. Furthermore, although the percentage of CD45lowCD11b+ microglial cells remained unchanged between the different experimental groups, we observed that microglia of α-Syn rats shifted from a pro-inflammatory M1-like to a pro-resolving/anti-inflammatory M2-like immunophenotype upon RvD1 treatment, in terms of modulation of their respective M1 (CD68, CD86, MHC-II) and M2 (CD206, TREM2) markers. These results suggest that RvD1 is able to delay disease progression by blunting neuroinflammation and inducing a microglia- driven pro-resolving response