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Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.

Background Parkinson’s disease (PD) is a genetically complex disorder in which combinations of heterozygous risk variants may contribute to pathogenesis. Many PD risk loci encode lysosomal genes, such as GBA1 , a common and potent risk factor, conferring at least a 5-fold increase. However, the mechanisms of GBA1 penetrance remain poorly understood. Methods Using Drosophila melanogaster , we performed a genetic interaction screen of lysosomal storage disorder (LSD) genes to identify dominant modifiers of Gba1b (fly homolog of GBA1 ). Age-dependent locomotor assessments, electroretinograms (ERG), transmission electron microscopy (TEM) analyses and quantification of dopaminergic (DA) neurons were used to assess the neurodegenerative phenotypes of double heterozygous animals. By combining immunostaining, lipidomics, metabolomics and pharmacological approaches we showed how partial loss of anne (fly homolog of ATP13A2 ) and Gba1b drives neurodegeneration. By interrogating genetic data from local and international PD cohorts we identified double heterozygous pathogenic variants in ATP13A2 and GBA1 in individuals with PD. Results We show that anne is expressed in neurons, whereas Gba1b is expressed in glia. Flies heterozygous for anne exhibit mild neurodegenerative phenotypes, and Gba1b strongly enhances this haploinsufficiency. Double heterozygous ( Gba1b T2A /+;anne T2A /+ ) flies exhibit a slow and progressive neurodegeneration associated with accumulation and impaired acidification of lysosomes in photoreceptors and other neurons. Obvious morphological defects are first observed in glia at day 15 after eclosion and include vacuolization and neuronal detachment. These defects are accompanied by an elevation of glucosylceramide (GlcCer) and followed by loss of neuronal function and degenerative features by day 30. These phenotypes are neuronal activity-dependent. The neurodegenerative phenotypes are rescued by: ML-SA1, an agonist of the lysosomal TRPML1 channel that has been reported to promote lysosomal membrane trafficking; myriocin, a compound that inhibits GlcCer production; and DFMO, a drug which inhibits polyamine synthesis. Based on surveys of genetic data, we identify multiple PD cases harboring digenic variants in GBA1 and ATP13A2 . Conclusions Our study reveals that partial loss of Gba1b in glia and anne in neurons synergistically disrupts lysosomal pH and neuron-glia GlcCer homeostasis, triggering neurodegeneration. Our results provide evidence that GBA1 penetrance is influenced by additional genetic modifiers, consistent with a putative digenic mechanism for GBA1 -PD penetrance. These findings highlight lysosomal acidification, sphingolipid clearance, and polyamine regulation as critical intervention points in digenic PD.

Glial cells are indispensable components of the peripheral nervous system (PNS), exerting diverse regulatory functions crucial for neuronal health and function. From myelination and synaptic modulation to immune regulation, glia actively participate in maintaining PNS homeostasis and responding to pathological insults. Further elucidating the roles of glial cells in peripheral nerve disorders holds promise for developing targeted therapeutic interventions to alleviate symptoms and improve patient outcomes. The aim of this article was to review the multifaceted functions of PNS glia in shaping nervous system function and their intricate involvement in various neuropathologies, including peripheral neuropathies, neuroinflammatory conditions, and gastrointestinal disorders. Understanding the underlying mechanisms of glial dysfunction offers opportunities for developing targeted therapeutic interventions aimed at preserving nerve function, attenuating neuroinflammation, and restoring gastrointestinal homeostasis. Growing research on PNS glia underlines their indispensable role and highlights the potential of therapeutic strategies targeting glial dysfunction in revolutionising the management of nervous system disorders, offering hope for improved patient outcomes and quality of life.

Diabetes is a chronic metabolic condition associated with high levels of blood glucose which leads to serious damage to the heart, kidney, eyes, and nerves. Elevated blood glucose levels damage brain function and cognitive abilities. They also lead to various neurological and neuropsychiatric disorders, including chronic neurodegeneration and cognitive decline. High neuronal glucose levels can cause drastic neuronal damage due to glucose neurotoxicity. Astrocytes, a type of glial cell, play a vital role in maintaining brain glucose levels through neuron–astrocyte coupling. Hyperglycemia leads to progressive decline in neuronal networks and cognitive impairment, contributing to neuronal dysfunction and fostering a neurodegenerative environment. In this review, we summarize the various connections, functions, and impairments of glial cells due to metabolic dysfunction in the diabetic brain. We also summarize the effects of hyperglycemia on various neuronal functions in the diabetic brain.

Astrocytes play a wide variety of roles in the central nervous system (CNS). Various facets of astrocyte-neuron interplay, investigated for the past few decades, have placed these most abundant and important glial cell types to be of supreme importance for the maintenance of the healthy CNS. Interestingly, glial dysfunctions have proven to be the major contributor to neuronal loss in several CNS disorders and pathologies. Specifically, in the field of neuroAIDS, glial dysfunction–mediated neuronal stress is a major factor contributing to the HIV-1 neuropathogenesis. As there is increasing evidence that astrocytes harbor HIV-1 and serve as “safe haven” for the dormant virus in the brain, the indirect pathway of neuronal damage has taken over the direct neuronal damage in its contribution to HIV-1 neuropathogenesis. In this review, we provide a brief insight into the astrocyte functions and dysfunctions in different CNS conditions with an elaborated insight into neuroAIDS. Detailed understanding of the role of astrocytes in neuroAIDS will help in the better therapeutic management of the neurological problems associated with HIV-1 patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model.

Background The acupuncture or electroacupuncture (EA) shows the therapeutic effect on various neurodegenerative diseases. This effect was thought to be partially achieved by its ability to alleviate existing neuroinflammation and glial dysfunction. In this study, we systematically investigated the effect of EA on abnormal neurochemical changes and motor symptoms in a mouse neurodegenerative disease model. Methods The transgenic mouse which expresses a mutant α-synuclein (α-syn) protein, A53T α-syn, in brain astrocytic cells was used. These mice exhibit extensive neuroinflammatory and motor phenotypes of neurodegenerative disorders. In this study, the effects of EA on these phenotypic changes were examined in these mice. Results EA improved the movement detected in multiple motor tests in A53T mutant mice. At the cellular level, EA significantly reduced the activation of microglia and prevented the loss of dopaminergic neurons in the midbrain and motor neurons in the spinal cord. At the molecular level, EA suppressed the abnormal elevation of proinflammatory factors (tumor necrosis factor-α and interleukin-1β) in the striatum and midbrain of A53T mice. In contrast, EA increased striatal and midbrain expression of a transcription factor, nuclear factor E2-related factor 2, and its downstream antioxidants (heme oxygenase-1 and glutamate-cysteine ligase modifier subunits). Conclusions These results suggest that EA possesses the ability to ameliorate mutant α-syn-induced motor abnormalities. This ability may be due to that EA enhances both anti-inflammatory and antioxidant activities and suppresses aberrant glial activation in the diseased sites of brains.

Recent studies highlight the presence of systemic toxicity as an integral dimension of bipolar disorder pathophysiology, possibly linking this mood disorder with other medical conditions and comorbidities. This review summarizes recent findings on possible peripheral biomarkers of illness activity, with a focus on neurotrophins, inflammation and oxidative stress. The possible mechanisms underlying the systemic toxicity associated with acute episodes in bipolar disorder are also discussed. Finally, the authors outline novel therapies that emerge from this new research and the assessment of multiple biomarkers as a potential approach to improving management strategies in bipolar disorder.

Microbiota-derived hydrogen sulfide (H2S) plays a crucial role in modulating the gut–brain axis, with significant implications for neurodegenerative diseases such as Alzheimer’s and Parkinson’s. H2S is produced by sulfate-reducing bacteria in the gut and acts as a critical signaling molecule influencing brain health via various pathways, including regulating inflammation, oxidative stress, and immune responses. H2S maintains gut barrier integrity at physiological levels and prevents systemic inflammation, which could impact neuroinflammation. However, as H2S has a dual role or a Janus face, excessive H2S production, often resulting from gut dysbiosis, can compromise the intestinal barrier and exacerbate neurodegenerative processes by promoting neuroinflammation and glial cell dysfunction. This imbalance is linked to the early pathogenesis of Alzheimer’s and Parkinson’s diseases, where the overproduction of H2S exacerbates beta-amyloid deposition, tau hyperphosphorylation, and alpha-synuclein aggregation, driving neuroinflammatory responses and neuronal damage. Targeting gut microbiota to restore H2S homeostasis through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation presents a promising therapeutic approach. By rebalancing the microbiota-derived H2S, these strategies may mitigate neurodegeneration and offer novel treatments for Alzheimer’s and Parkinson’s diseases, underscoring the critical role of the gut–brain axis in maintaining central nervous system health.

The concept of gliodegenerative diseases has not been widely established although there is accumulating evidence that glial cells may represent a primary target of degenerative disease processes. In the central nervous system (CNS), examples that provide a \"proof of concept\" include at least one alpha-synucleinopathy, multiple system atrophy (MSA), but this disease is conventionally discussed under the heading of \"neurodegeneration\". Additional evidence in support of primary glial affection has been reported in neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and transmissible spongiform encephalopathies. Based on biochemical, genetic and transcriptomic studies it is also becoming increasingly clear that the molecular changes measured in whole tissue extracts, e.g. obtained from Parkinson's disease brain, are not based on a purely neuronal contribution. This important evidence has been missed in cell culture or laser capture work focusing on the neuronal cell population. Studies of animal and in vitro models of disease pathogenesis additionally suggest glial accountability for some CNS degenerative processes. This review provides a critical analysis of the evidence available to date in support of the concept of gliodegeneration, which we propose to represent an essential although largely disregarded component of the spectrum of classical \"neurodegeneration\". Examples from the spectrum of alpha-synucleinopathies are presented.