Sarah Steffen

Background: Alzheimer disease (AD) is a progressive neurodegenerative disorder that significantly impacts cognitive functioning and episodic memory.¹ Traditionally defining and associated characteristics of AD include amyloid-β (Aβ) plaque burden, hyperphosphorylated tau tangles, ventriculomegaly, and cerebral cortex and hippocampal atrophy.^1-3 AD is widely recognized as a multifactorial disease influenced by factors including genetic mutations, aging, chronic diseases such as CAD, and many others.^2-4 Emerging research highlights immune dysregulation in both the central nervous system (CNS) and peripheral compartments as a driver of AD. Peripheral inflammation, particularly splenic immune signaling, can impair the blood-brain barrier (BBB) integrity, activate proinflammatory microglia, and drive neuroinflammation.^1-3 Tumor necrosis factor superfamily member 10 (TNFSF10, also known as TRAIL) is a proinflammatory and proapoptotic cytokine that has emerged as a potential mediator linking peripheral immune dysfunction to central neurodegeneration in AD. ^5-7 TNFSF10 binds DR4 (TNFRSF10A) and DR5 (TNFRSF10B), activating intracellular cascades involving NF-κB and caspases. This dual signaling promotes the transcription of proinflammatory cytokines and apoptosis, which both contribute to promoting and sustaining an inflammatory state that drives neuronal cell death, BBB disruption, and microglial activation.^7,8

Objective: This review examines the mechanisms by which TNFSF10 signaling influences immune activity across the CNS and the periphery to drive AD pathogenesis and progression.

Search Methods: An online search in the PubMed database was conducted for literature reviews and primary literature articles published from 2019 to 2025 using the keywords “TNFSF10,” “TRAIL,” “Alzheimer disease,” “neuroinflammation,” and “immune response.” Articles focusing on TNFSF10 signaling in mouse models of AD and human transcriptomic datasets were included.

Results: In triple transgenic AD mouse models, TNFSF10 upregulation increased CNS proinflammatory cytokine expression (TNF-α, IL-1β), microglial activation, and Aβ plaque burden. Neutralizing TNFSF10 with monoclonal antibody treatment reduced these markers, restored anti-inflammatory IL-10 expression, and decreased hippocampal neuroinflammation.^5,7 Retinal studies further demonstrated that TNFSF10 modulated the proinflammatory microRNA-155 pathway, reducing proinflammatory microglial activation and proinflammatory cytokine expression following antibody neutralization intervention.³ Peripheral immune effects were also observed: TNFSF10 neutralization improved T-regulatory (Treg) cell function in the spleen and reduced expression of inflammatory mediators, such as COX2 and iNOS.^1,4 In a separate splenectomy study, removal of the spleen led to worsened AD pathology and reduced circulating monocytes, underscoring the spleen’s role in immune homeostasis and Aβ clearance in AD pathogenesis.⁹ Given that TNFSF10 signaling influences splenic immune cell function, including monocyte activation and Treg regulation, these findings indirectly support the importance of the spleen as a key site where TNFSF10 activity may impact CNS inflammation and amyloid burden.⁹ Lastly, a 2024 bioinformatics study discovered upregulation of TNFRSF10B, a TNFSF10 receptor, in human AD brain tissue, supporting the translational relevance of TNFSF10 signaling in human AD.⁸

Conclusions: Collectively, these findings position TNFSF10 as a key mediator of immune dysregulation in AD and support reframing AD as an immunologically integrated disorder spanning both the CNS and peripheral compartments. Targeting this immune axis may enable more effective, system-wide therapeutic strategies. Preclinical studies demonstrate that anti-TNFSF10 interventions reduce neuroinflammation and confer neuroprotection, while human transcriptomic data suggest diagnostic and therapeutic potential. Future research should prioritize noninvasive methods for monitoring TNFSF10 activity and further clarifying its role in human AD pathophysiology.

Works Cited:

1. Xie J, Van Hoecke L, Vandenbroucke RE. The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology. Front Immunol. 2022;12:796867. Published 2022 Jan 6. doi:10.3389/fimmu.2021.796867
2. Zhang Q, Yang G, Luo Y, Jiang L, Chi H, Tian G. Neuroinflammation in Alzheimer’s disease: insights from peripheral immune cells. Immun Ageing. 2024;21(1):38. doi:10.1186/s12979-024-00445-0
3. Walker KA, Le Page LM, Terrando N, Duggan MR, Heneka MT, Bettcher BM. The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap. Mol Neurodegener. 2023;18(1):37. doi:10.1186/s13024-023-00627-2
4. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules. 2020;25(24):5789. doi:10.3390/molecules25245789
5. Cantone AF, Burgaletto C, Di Benedetto G, et al. Rebalancing Immune Interactions within the Brain-Spleen Axis Mitigates Neuroinflammation in an Aging Mouse Model of Alzheimer’s Disease. J Neuroimmune Pharmacol. 2025;20(1):15. doi:10.1007/s11481-025-10177-7
6. Burgaletto C, Platania CBM, Di Benedetto G, et al. Targeting the miRNA-155/TNFSF10 network restrains inflammatory response in the retina in a mouse model of Alzheimer’s disease. Cell Death Dis. 2021;12(10):905. doi:10.1038/s41419-021-04165-x
7. Di Benedetto G, Burgaletto C, Carta AR, et al. Beneficial effects of curtailing immune susceptibility in an Alzheimer’s disease model. J Neuroinflammation. 2019;16(1):166.fdoi:10.1186/s12974-019-1554-9
8. Zhang G, Sun S, Wang Y, Zhao Y, Sun L. Unveiling Immune-related feature genes for Alzheimer’s disease based on machine learning. Front Immunol. 2024;15:1333666. doi:10.3389/fimmu.2024.1333666
9. Yu ZY, Chen DW, Tan CR, et al. Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer-type pathogenesis. Aging Cell. 2022;21(1):e13533. doi:10.1111/acel.13533