The Role of Glial Cells in the Pathophysiology and Treatment of Alzheimer's Disease

Simone M. Crivelli^1*Zainuddin Quadri²Daan van Kruining³Pilar Martinez³Erhard Bieberich²Jean-Yves Chatton^1*

• ¹Université de Lausanne, Lausanne, Switzerland
• ²University of Kentucky, Lexington, United States
• ³Universiteit Maastricht, Maastricht, Netherlands

From mapping the research landscape on astrocyte function in AD to mechanistic insights. Two bibliometric studies provide a quantitative overview of the field's growing focus on glia. One study, centered on glial fibrillary acidic protein (GFAP), highlights increasing interest in astrocyte reactivity, with persistent hotspots in oxidative stress and neuroinflammation, and rising attention to blood-based GFAP as a scalable biomarker for AD screening ([Zou et al.]). A complementary "top-100" analysis of astrocyte-related AD studies reveals a shift from descriptive to mechanistic themes, such as "activation," "Aβ," and pathwaylevel analysis, while identifying key institutions and researchers driving this change ([He et al.]). Together, these studies show a field increasingly focused on testable mechanisms and clinically relevant markers of glial dysfunction.Glial failure at the intersection of genes and metabolism. Mechanistic studies in this collection converge on two upstream regulators of glial function: lipid/genetic risk and cellular energy balance. One study using ApoE-knockout mice shows that ApoE deficiency disrupts microglial and astrocytic homeostasis in an age-dependent manner, increasing inflammation and impairing Aβ clearance in both brain and retina. Diet worsens these effects, and tear-based miRNAs emerge as potential noninvasive markers of glial stress ([Wijesinghe et al.]). A focused review on mitochondrial uncoupling protein 4 (UCP4) places astrocyte bioenergetics at the forefront: reduced UCP4 in AD, and evidence that boosting astrocyte-specific UCP4 restores metabolic balance and protects neuronal structure, suggest mitochondrial uncoupling as a promising therapeutic target ([Crivelli et al.]).Microglial mechanosensing reframes plaque biology. Beyond chemical signals, microglia also respond to the physical environment of the AD brain. A state-of-the-art review of the Piezo1 mechanosensitive channel shows how microglia migrate toward the stiffer regions around amyloid plaques and translate mechanical cues into calcium-driven responses that affect phagocytosis, cytokine release, and plaque burden ([Ikiz et al.]). Notably, Piezo1 can be modulated by small molecules and lifestyle factors (e.g., fatty acids, exercise, ultrasound), expanding the therapeutic toolkit beyond traditional receptor-based approaches. Mechanosensing thus adds a new layer to our understanding of microglial control over aggregate clearance and inflammation.Gut-glia axes: peripheral levers for central immunity. Two reviews explore how the microbiota-gut-brain axis influences glial states in AD. Dysbiosis alters microglial activation and astrocyte function through microbial metabolites (e.g., short-chain fatty acids) and pathogen-associated signals (e.g., lipopolysaccharide), affecting NF-κB/TLR4 signaling, oxidative stress, and synaptic pruning. The therapeutic implication is clear: prebiotics, probiotics, and postbiotics may help shift glial cells toward homeostatic states, reducing neuroinflammation and improving clearance and metabolic support ([Wu et al.] and [Patricio Martínez et al.]). Translational studies in this collection show how glial pathways can be targeted therapeutically. A comprehensive review of acupuncture in AD reports consistent modulation of microglial phenotypes:from pro-inflammatory to reparativevia TLR4/NF-κB, NLRP3 inflammasome, and TREM2 signaling, with additional effects on complement-mediated synaptic pruning ([Liu et al.]). The Piezo1 framework suggests mechanotherapeutic and bioelectric strategies to enhance microglial phagocytosis ([Ikiz et al.]), while the UCP4 perspective supports astrocyte-targeted metabolic interventions to restore trophic support and redox balance ([Crivelli et al.]).The eight articles included in this Research Topic collectively foster a glia-centric understanding of AD. In summary: bibliometric mapping shows where the field is investing; mechanistic studies reveal how lipid genetics and mitochondrial metabolism destabilize glial function; biophysical and peripheral perspectives (Piezo1 and the gut-brain axis) broaden the therapeutic landscape; and translational examples demonstrate that reprogramming glia is both feasible and promising.