Aug 2026· MedComm· Vol 7· 0 citations· 388 references
Medicine
TL;DR
This review examines RCD as an integrated pathogenic network in major NDs as well as evaluating emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system.
Abstract
ABSTRACT Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease‐specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B‐cell lymphoma 2 (BCL2) family signaling, receptor‐interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain‐like protein activation, NOD‐like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4‐linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease‐specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.
This review systematically elucidates the core mechanisms of the JAK/STAT pathway in NDDs, including the regulation of microglial and astrocytic reactivity, the impact on blood–brain barrier integrity, and involvement in energy metabolism abnormalities.
Hai-Xia Yang, Bowei Su, Ya-Nan Bao et al.· Frontiers in Aging Neuroscie...· 0 citations
A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.
Nagaraj Rangappa, Riddhi Upadhyay, Nathish Lakshman et al.· Advances in Protein Chemistr...· 0 citations
Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.
Haixia Wang, Ruiming Wen, Emily Parker et al.· Cell communication and signa...· 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.
Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.
Xinkai Wu, Qiuyan Ye, Min Zi et al.· Molecular and cellular neuro...· 0 citations
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized primarily by progressive cognitive impairment, whose pathogenesis involves multiple pathological processes including protein deposition, metal homeostasis dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. In recent years, metabolism-related cell death modalities such as ferroptosis, cuproptosis, and disulfidptosis have gradually been recognized as potentially involved in neuronal damage in Alzheimer’s disease. This review summarizes the fundamental mechanisms of ferroptosis, cuproptosis, and disulfidptosis, along with their research evidence in AD. Ferroptosis is primarily driven by iron imbalance, lipid peroxidation buildup, and impaired GPX4 defense. This process exhibits a bidirectional amplification loop with Aβ and tau pathologies. Cuproptosis contributes to neuronal damage through abnormal copper accumulation, FDX1-related mitochondrial protein lipoylation dysfunction, loss of iron-sulfur cluster proteins, and proteotoxic stress. Disulfidptosis links glucose metabolism disorders, insufficient reducing power, and actin cytoskeleton vulnerability, providing novel insights into metabolic stress and structural damage in AD. Furthermore, the three modes of cell death can undergo cross-regulation through the SLC7A11–NADPH–GSH/GPX4 axis, the FDX1–DLAT/DLST–iron-sulfur cluster axis, as well as upstream factors such as p53, NRF2, and AMPK. Metabolic cell death may constitute a critical pathological network in AD. Targeting these death pathways and their shared hubs is expected to provide new directions for disease stratification, biomarker development, and disease-modifying therapies.
Shuyu Ding, Zihan Guo, Hengyu Ji et al.· Frontiers in Cell and Develo...· 0 citations