New knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD is summarized, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.
Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, characterized by progressive cognitive decline, memory impairment, and behavioral dysfunction. Despite extensive research, effective disease-modifying therapies remain limited, largely due to incomplete understanding of its complex and multifactorial pathogenesis. Increasing evidence now highlights chronic neuroinflammation as a central contributor to AD progression, shifting focus from a purely proteinopathy-based model toward an integrated neuroimmune perspective. Among key inflammatory pathways, the NLRP3 inflammasome has emerged as a critical innate immune signaling platform that links pathological protein aggregation to sustained neuroinflammatory responses in the central nervous system. Activation of the NLRP3 inflammasome is triggered by multiple Alzheimer’s disease–associated pathological stimuli, including amyloid-β accumulation, tau pathology, autophagy dysfunction, mitochondrial impairment, oxidative stress, and endoplasmic reticulum stress. These cellular disturbances converge to promote assembly of the inflammasome complex and activation of caspase-1. Activated caspase-1 mediates the proteolytic maturation and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), both of which play central roles in amplifying neuroinflammatory signaling, promoting synaptic dysfunction, and contributing to neuronal injury. Consequently, IL-1β and IL-18 have gained increasing attention as potential biomarkers for disease severity, progression, and inflammatory burden in Alzheimer’s disease. In addition, inflammasome-specific markers such as apoptosis-associated speck-like protein containing CARD (ASC) specks provide further mechanistic and diagnostic evidence of active inflammasome signaling in neurodegeneration. Preclinical studies using cellular and animal models have demonstrated that pharmacological inhibition of the NLRP3 inflammasome can reduce neuroinflammation, attenuate neuropathological changes, and improve cognitive performance. However, despite these promising findings, clinical translation remains limited due to challenges including inadequate blood–brain barrier penetration, systemic immune modulation risks, and the absence of reliable biomarker-guided patient stratification strategies. This review critically examines the molecular mechanisms underlying NLRP3 inflammasome activation in Alzheimer’s disease, its interaction with pro-inflammatory cytokine networks, and the emerging role of inflammasome-related biomarkers in disease characterization. Furthermore, current therapeutic strategies targeting the NLRP3 pathway are discussed, along with key translational barriers and future directions for developing biomarker-driven immunomodulatory therapies in Alzheimer’s disease.
Hira Shabbir· Scholars International Journ...· 0 citations
Alzheimer’s disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a “cellular state–pathological network–therapeutic window” framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7–NLRP3 and cGAS–STING, CSF1R/complement, and TNF–TNFR1–RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.
Lianjing Xu, Ying Zhang, Li Jiang et al.· Frontiers in Cellular Neuros...· 0 citations
Highlights What are the main findings? NETs contribute to neuroinflammation by promoting blood–brain barrier disruption and the amplification of inflammatory signaling in several neurodegenerative diseases. Dysregulated NET formation is increasingly recognized as a mechanistic link between innate immune activation and neuronal injury in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. What are the implications of the main findings? Targeting the NETosis pathways represents a promising therapeutic strategy to modulate neuroinflammation and reduce neurovascular damage in neurodegenerative disorders. Emerging approaches, including PAD4 inhibition, DNase-mediated NET degradation, and modulation of oxidative signaling pathways, may provide new avenues for therapeutic intervention. Abstract Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.
Alzheimer’s disease (AD) is the most common cause of dementia and major public-health challenge in aging societies worldwide. Accumulating evidence suggests that olfactory and visual deficits can precede overt cognitive symptoms and are closely associated with amyloid-β deposition, pathological tau phosphorylation, and disease progression. Early sensory abnormalities in AD likely arise from converging pathological processes. Among these, chronic neuroinflammation marked by microglial and astrocytic reactivity, inflammasome activation and increased pro-inflammatory mediators might play a pivotal role linking sensory-circuit injury to neurodegeneration. A coherent synthesis of the inflammatory mechanisms underlying early olfactory and visual impairment in AD remains limited, and putative molecular pathways and interventions have not been fully integrated. We aimed to identify AD-related olfactory and visual or retinal abnormalities, combine core inflammatory pathways and their interactions with amyloid-β and tau pathology, and summarize actionable targets and candidate interventions along a “receptor–intracellular signaling-inflammasome-effector” axis, to inform earlier-stage detection and mechanism-guided intervention in AD.
Yanjiao Xu, Guimei Zhang, Xinran Cui et al.· Frontiers in Aging Neuroscie...· 0 citations
Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder affecting over 55 million individuals worldwide, characterised by Amyloid beta (Aβ) plaques, neurofibrillary tangles, and sustained neuroinflammation. While amyloid- and tau-targeted therapies have dominated therapeutic research, their limited clinical efficacy has intensified focus on neuroinflammation as a central and modifiable disease mechanism. This review synthesises current understanding of neuroinflammatory pathogenesis in AD, with emphasis on Microglial polarisation (M1/M2), Disease-Associated Microglia (DAM), TREM2 signalling, and reactive astrocyte conversion. This paper further evaluates pharmacological strategies targeting these pathways, including cytokine inhibitors (TNF-α and IL-6 blockade), microglial modulators (CSF-1R inhibitors, TREM2 agonistic antibodies), and emerging innate immune targets (cGAS-STING pathway inhibitors, and S-palmitoylation inhibitors). Despite strong preclinical rationale, clinical translation has been impeded by Blood-Brain Barrier (BBB) penetration challenges, intervention timing, peripheral immunosuppression risks, and the biological redundancy of neuroimmune networks. Future therapeutic success will likely require combination approaches, CNS-targeted delivery systems, and biomarker-guided patient stratification to fully exploit the therapeutic potential of neuroinflammation-directed strategies in AD.
Zizhen Ren· Journal of Clinical Technolo...· 0 citations