The Immuno-Glial Connectome in Alzheimer's Disease: Integrating Central and Peripheral Inflammatory Networks.

Gopalakrishna PK, Che Mohd Nassir CMN, Anandan S, Hussan F, Dandala KCR, Sura S, Jagadeesan S, Mohd Moklas MA, Vishnumukkala T, Hein ZM

Cellular and molecular neurobiology 2026

Open on PubMed

UNLABELLED: Alzheimer’s disease (AD) is increasingly recognized as a disorder of dysregulated neuroimmune connectivity rather than isolated proteinopathy. The immuno-glial connectome, the dynamic interplay between microglia, astrocytes, and peripheral immune systems, constitutes a central driver of disease initiation and progression. Emerging single-cell and spatial transcriptomic studies reveal heterogeneous glial subpopulations with context-dependent transcriptional programs governed by TREM2–APOE, NF-κB, JAK/STAT, and NLRP3 inflammasome signaling. These networks converge to sustain chronic inflammation, impair amyloid-β clearance, and accelerate tau pathology. Complement dysregulation (C1q–C3 axis) further promotes aberrant synaptic pruning, while cytokine feedback loops involving IL-1β, TNF-α, and IFN-γ amplify neurotoxicity. Beyond the brain, peripheral immune cells, monocytes, macrophages, T and B lymphocytes, and neutrophils breach the compromised blood–brain barrier (BBB), perpetuating inflammatory cascades. Parallelly, gut dysbiosis and microbial metabolites modulate microglial reactivity via the gut–brain axis (GBA), linking systemic inflammation to central immune activation. Recent advances in plasma and cerebrospinal biomarkers (GFAP, sTREM2, YKL-40, and neurofilament light chain) enable in vivo tracking of neuroinflammatory dynamics, bridging mechanistic research with clinical translation. Therapeutic strategies targeting the immuno-glial interface, including selective NLRP3 inhibitors, TREM2 agonists, anti-cytokine biologics, and microbiome modulation, are reshaping the therapeutic landscape. Framed through the concept of an immune–glial connectome, this review synthesizes how coordinated interactions among microglia, astrocytes, and peripheral immune cells converge to drive synaptic dysfunction, circuit-level disintegration, and cognitive decline in neurodegenerative disease, particularly in AD. GRAPHICAL ABSTRACT: An immuno-glial network in AD, where central glia, peripheral immune cells, and the gut–brain axis interact through cytokines, oxidative stress, and barrier dysfunction. These interrelated pathways amplify inflammation via NF-κB, JAK/STAT, and NLRP3 signaling, linking immune dysregulation to neurodegeneration. [Image: see text]

6 Figures Extracted

Fig. 1 PMC

Dynamic microglial activation programs and signaling networks in Alzheimer’s disease (AD). Under physiological conditions, microglia exist in a state ...

Fig. 2 PMC

Schematic representation of astrocytic activation and neuroinflammatory pathways in Alzheimer’s disease (AD). Exposure to amyloid-β (Aβ) or injury tri...

Fig. 3 PMC

Schematic representation of complement pathway activation in Alzheimer’s disease (AD). The three complement activation routes, classical (C1q binding ...

Fig. 4 PMC

Illustration of cytokine-mediated neuroinflammatory pathways linking gut–brain axis (GBA) dysfunction to Alzheimer’s disease (AD) pathology. Gut micro...

Fig. 5 PMC

Molecular mechanism of NLRP3 inflammasome activation in Alzheimer’s disease (AD). The schematic depicts the two-step activation process: (1) Priming (...

Fig. 6 PMC

Peripheral immune cell trafficking and interactions in Alzheimer’s disease (AD). In AD, blood-brain barrier (BBB) disruption, accompanied by increased...