Neuroglia

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies.

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways.

Background/Objectives: A healthy lifestyle based on a balanced diet promotes overall well-being and supports brain health, while the consumption of high-energy foods can negatively affect cognitive function, particularly during early developmental stages, such as adolescence. Astrocytes are essential for brain homeostasis, including modulation of neurogenesis in the hippocampus, a region involved in cognitive functions. The impact of short-term high-fat diet (HFD) exposure on astrocytes during adolescence remains unclear. In this study, we examined if brief periods of HFD influence astrocyte morphology, density, and territory volume and, in parallel, the maturation of doublecortin-positive (DCX⁺) cells in the dorsal hippocampus of adolescent male mice. Methods: We performed 3D reconstructions, analyzed morphometric features as well as other parameters of astrocytes and DCX⁺ cells following 1 week of HFD (1 w-HFD), 2 weeks of HFD (2 w-HFD), and 1 week of HFD followed by 1 week of return to a low-fat diet (1 w-HFD – 1w-LFD). Results: We observed that 1 w-HFD significantly increased astrocyte morphological complexity and density compared with the control group (1 w-LFD). After 2 w-HFD, astrocyte complexity declined, whereas density was unchanged. Notably, in the 1 w-HFD – 1 w-LFD group, astrocyte complexity was comparable to that of the 2 w-HFD group; density increased compared to both control groups (2 w-LFD and 2 w-HFD). Moreover, both 1 w- and 2 w-HFD impaired granular cell layer (GCL) DCX⁺ cells density and maturation, and a return to LFD after 1 w-HFD restored maturation but not density. Conclusions: Altogether, these data suggest that short-term HFD exposure has complex effects on GCL astrocytes and impairs DCX⁺ cell maturation in the dorsal hippocampus of adolescent mice.