Psychiatric disorders have long been associated with inflammation- either as prolonged mental illnesses leading to immune dysregulations or as psychiatric conditions arising from systemic inflammation. Physiologically, inflammation is one of the responses to bodily stress, however, the degree of inflammation depends on the type and duration of the stressor. Here, we focus on understanding both- inflammation-induced brain cellular response alterations and neuroinflammation caused by an underlying psychiatric condition. Apart from post-mortem brains, the closest approach by which one can recreate both these phenomena are by using patient-derived induced pluripotent stem cells (IPSCs), as the brain tissue is inaccessible. Therefore, we focus on studies using IPSC-derived brain cells from patients to model inflammation across psychiatric conditions. Unlike any other available model system, IPSCs hold a major advantage of carrying patients' genetic background that is crucial to understand disorders as complex and enigmatic as psychiatric disorders. When knowledge on patients' genetic risks and environmental exposures are integrated into patient iPSC-derived brain cellular models, it holds enormous potential to delineate psychiatry related pathophysiology from other comorbidities. Therefore, understanding the cellular responses to inflammation and treatment helps us refine the existing therapeutic strategies and initiate early interventions to better manage psychiatric disorders.
Microglia perform the function of CNS macrophages and act as the primary immune cells in the brain. They surveil the environment, phagocytose cellular debris, maintain homeostasis and respond to tissue damage. While under physiological conditions they play a role in supporting neurons, activated microglia participate directly in the degeneration of neurons in the substantia nigra, as the hallmark of the Parkinsons disease (PD). Their detrimental effects result from direct phagocytosis of dopaminergic neurons as well as via neuroinflammation and release of toxic reactive oxygen and nitrogen species. This pathological shift is driven by a complex interplay of genetic predispositions, such as LRRK2 and GBA mutations, and environmental triggers like toxins and gut dysbiosis.A central mechanism of this neurodegeneration involves extracellular α-synuclein acting as a danger signal (DAMP), which activates microglial Toll-like receptors (e.g., TLR2) to initiate a severe inflammatory cascade. Furthermore, the extreme biophysical stability of aggregated α-synuclein overwhelms the microglial endolysosomal network, leading to lysosomal failure, "frustrated phagocytosis," and the active propagation of the disease via exosomal shedding. Relieving this maladaptive chronic neuroinflammation is a primary therapeutic goal. Modern strategies aim to break this vicious cycle through precise interventions like NLRP3 inflammasome inhibition and autophagy enhancement. Concurrently, advanced fluid biomarkers, such as seed amplification assays (SAA), alongside multidimensional neuroimaging techniques (PET, SPECT, MRI), are proving crucial for detecting these early microglial and pathological changes to guide personalized, disease-modifying therapies of PD.
Parkinson's disease (PD) pathology extends well beyond dopaminergic neuronal loss, with glial cells-microglia and astrocytes-emerging as active architects of α-synuclein spread rather than passive bystanders. This review synthesises current evidence on how mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), the most common genetic cause of familial PD, fundamentally corrupt glial handling of extracellular α-synuclein. We first outline the biology of extracellular α-synuclein-its cellular sources, conformational spectrum, prion-like propagation mechanisms, and principal glial clearance routes-before examining LRRK2 domain architecture, its downstream Rab GTPase signalling cascade, and the cellular processes it governs in glia. We then detail how LRRK2 mutations reconfigure microglial responses: driving constitutive NLRP3 inflammasome priming, impairing phagolysosomal degradation of α-synuclein aggregates, and redirecting phagocytosed cargo into pathogenic exosomal release via the LRRK2-Rab10-LYTL axis. In astrocytes, LRRK2 mutations disrupt annexin A2-mediated phagocytosis, impair chaperone-mediated autophagy and lysosomal acidification, deplete membrane cholesterol through Rab8A/Rab10 hyperphosphorylation, compromise glutamate transporter surface expression, and promote the secretion of phospho-α-synuclein-enriched extracellular vesicles that are neurotoxic to co-cultured dopaminergic neurons. Crucially, dysfunctional microglia and astrocytes do not operate independently-they form a self-amplifying feed-forward circuit in which microglial cytokines (IL-1α, TNF-α, C1q) drive A1 astrocyte conversion, tunnelling nanotube-mediated aggregate exchange propagates rather than resolves α-synuclein burden, and successive waves of neuronal death perpetuate the cycle. We highlight that these mechanisms are mutation-specific: the GTPase-domain variant I1371V, characterised through our group's patient-derived iPSC platform, drives qualitatively distinct membrane and metabolic dysfunction compared with the kinase-domain variant G2019S, underscoring the need for variant-tailored therapeutic strategies. We review human iPSC-based models-including microglia-like cells, midbrain-patterned astrocytes, and 3D midbrain organoids-that have proven indispensable for resolving cell-autonomous from non-cell-autonomous contributions of LRRK2 mutations. Finally, we evaluate emerging therapeutic strategies targeting LRRK2 kinase activity, NLRP3 inflammasome activation, extracellular α-synuclein immunotherapy, and glial lysosomal enhancement, including intranasal mesenchymal stromal cell-derived small extracellular vesicles. We conclude by identifying key unanswered questions regarding the relative dominance of microglial versus astrocytic clearance at different disease stages, the full pathogenic landscape of understudied LRRK2 variants, and the tractability of glial biomarkers as pharmacodynamic endpoints in clinical trials.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Other neuropathological hallmarks include α-synuclein aggregation, Lewy bodies, Lewy neurites, and neuroinflammation in the brain. It has been proposed that the α-synuclein pathology starts in the gut with the non-motor symptoms, and then it propagates to the brain via the vagus nerve causing motor symptoms. The immune cells in the brain, namely microglia and astrocytes trigger innate immune responses and the infiltrating T cells are a part of adaptive immune response. The production of cytokines and chemokines enhances neuroinflammation. In the periphery, the monocytes and CD4+ and CD8+ T cells activation increases, causing inflammation. As inflammation is the key pathological hallmark of PD, it has emerged as an attractive target for immunotherapies. The active and passive immunotherapeutic drugs target the α-syn aggregates to overcome neuroinflammation and other motor and non-motor symptoms.
Neuroinflammation shaped by aberrant cellular interactions represents a hallmark of neurodegenerative diseases of the central nervous system (CNS). Microglia are specialized tissue-resident macrophages that reside in the CNS parenchyma and have emerged as central regulators of this aberrant cellular crosstalk. They integrate local signals and orchestrate the cellular interaction networks that underlie disease progression. Recent advances in single-cell and single-nucleus omics, in combination with spatially resolved approaches, have substantially advanced our understanding of microglial dynamics in neurodegeneration. These technological and conceptual advances have revealed an unexpected diversity of disease-associated microglial states and highlighted microglia as central organizers of multicellular interaction networks within diseased CNS tissue. In this chapter, we discuss how these advances have reshaped our understanding of microglia-centered cellular crosstalk in neurodegeneration. We focus on the diversification of neurodegenerative CNS microglial states, the interaction of microglia with neurons, glial cells, adaptive immune cells, and the vasculature. We further discuss how this framework provides a basis for therapeutic strategies aimed at modulating, replacing, or reprogramming microglia in neurodegenerative disease.
