It is illustrated 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.
Abstract
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.
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.
R. Kumar, Kamaljeet, Sourabh Kosey· InflammoPharmacology· 0 citations
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
The protective and deleterious roles of NETs are investigated and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity are investigated, offering valuable insights for potential applications in clinical practice.
Alzheimer's disease (AD) is one of the most common types of neurodegenerative diseases. Its pathogenesis involves the interaction of multiple factors, including β-amyloid deposition, excessive tau protein phosphorylation, neuroinflammation, and synaptic dysfunction. Among these, neuroinflammation is widely recognized as a key factor driving the onset and progression of AD. As the two main types of glial cells in the central nervous system, microglia and astrocytes play central roles in the regulation of neuroinflammation. This paper systematically reviews the structural characteristics and functional states of microglia and astrocytes in AD-related neuroinflammation, as well as their interactions with Aβ and tau pathologies. Both types of glial cells exhibit a bidirectional transition from a protective to a damaging phenotype. In the early stage, they exert neuroprotective effects by phagocytosing and clearing abnormal proteins and releasing neurotrophic factors. Under sustained inflammatory stimulation, both gradually shift to a pro-inflammatory activated state, releasing large amounts of inflammatory factors, disrupting the blood-brain barrier and glymphatic system, and abnormally phagocytosing synaptic structures, forming a vicious cycle in which pathological protein deposition and excessive glial cell activation mutually exacerbate each other. More importantly, the two types of glial cells interact through various pathways such as cytokines, complement pathways, and signaling molecules, jointly amplifying the inflammatory cascade. This paper also summarizes therapeutic strategies for drugs targeting these two glial cells, including cholinesterase inhibitors, NMDA receptor antagonists, non-steroidal anti-inflammatory drugs, and biological agents targeting Aβ and tau proteins. In conclusion, functional abnormalities and interactive disorders of microglia and astrocytes are the core driving factors of AD neuroinflammation. An in-depth understanding of the molecular mechanisms underlying their interaction will provide a new breakthrough for shifting AD treatment from symptomatic management to etiological eradication.
Ruoyu Liu· Theoretical and Natural Scie...· 0 citations
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.
Zizhen Ren· Journal of Clinical Technolo...· 0 citations
The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.
S. Papelian· International Journal of Dev...· 0 citations
