An official website of the United States government
Alzheimer's disease (AD) is a progressive and neurodegenerative disease, predominantly causing dementia. Despite increasing clinical evidence suggesting the involvement of peripheral immune cells such as monocytes in AD pathology, the dynamic penetration and infiltration of monocytes crossing blood–brain barrier (BBB) and inducing neuroinflammation is largely understudied in an AD brain. Herein, we engineer BBB-like microphysiological system (BBB-MPS) models for recapitulating the dynamic penetration and infiltration of monocytes in an AD patient's brain. Each BBB-MPS model can be engineered by integrating a functional BBB-like structure on a human cortical organoid using a 3D-printed device within a well of a plate. By coculturing these BBB-MPS models with monocytes from AD patients and age-matched healthy donors, we found that AD monocytes exhibit significantly greater BBB penetration and brain infiltration compared to age-matched control monocytes. Moreover, we also tested the interventions including Minocycline and Bindarit, and found they can effectively inhibit AD monocyte infiltration, subsequently reducing neuroinflammation and neuronal apoptosis. We believe these scalable and user-friendly BBB-MPS models may hold promising potential in modeling and advancing therapeutics for neurodegenerative and neuroinflammatory diseases.
more »
« less
This content will become publicly available on August 22, 2026
Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems
Increasing evidence strongly links neuroinflammation to Alzheimer’s disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in IL1B and CCL3 expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes’ role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases.
more »
« less
- Award ID(s):
- 2422149
- PAR ID:
- 10630422
- Publisher / Repository:
- Science Advances
- Date Published:
- Journal Name:
- Science Advances
- Volume:
- 11
- Issue:
- 34
- ISSN:
- 2375-2548
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
HIV latency regulation in monocytes and macrophages can vary according to signals directing differentiation, polarization, and function. To investigate these processes, we generated an HIV latency model in THP-1 monocytes and showed differential levels of HIV reactivation among clonal populations. Monocyte-to-macrophage differentiation of HIV-infected primary human CD14+ and THP-1 cells induced HIV reactivation and showed that virus production increased concomitant with macrophage differentiation. We applied the HIV-infected THP-1 monocyte-to-macrophage (MLat) model to assess the biological mechanisms regulating HIV latency dynamics during monocyte-to-macrophage differentiation. We pinpointed protein kinase C signaling pathway activation and Cyclin T1 upregulation as inherent differentiation mechanisms that regulate HIV latency reactivation. Macrophage polarization regulated latency, revealing proinflammatory M1 macrophages suppressed HIV reactivation while anti-inflammatory M2 macrophages promoted HIV reactivation. Because macrophages rely on reactive-oxygen species (ROS) to exert numerous cellular functions, we disrupted redox pathways and found that inhibitors of the thioredoxin (Trx) system acted as latency-promoting agents in T-cells and monocytes, but opposingly acted as latency-reversing agents in macrophages. We explored this mechanism with Auranofin, a clinical candidate for reducing HIV reservoirs, and demonstrated Trx reductase inhibition led to ROS induced NF-κB activity, which promoted HIV reactivation in macrophages, but not in T-cells and monocytes. Collectively, cell type-specific differences in HIV latency regulation could pose a barrier to HIV eradication strategies.more » « less
-
null (Ed.)Autism Spectrum Disorder (ASD) is a neurodevelopmental disease originating from combined genetic and environmental factors. Post-mortem human studies and some animal ASD models have shown brain neuroinflammation, oxidative stress, and changes in blood–brain barrier (BBB) integrity. However, the signaling pathways leading to these inflammatory findings and vascular alterations are currently unclear. The BBB plays a critical role in controlling brain homeostasis and immune response. Its dysfunction can result from developmental genetic abnormalities or neuroinflammatory processes. In this review, we explore the role of the Sonic Hedgehog/Wingless-related integration site (Shh/Wnt) pathways in neurodevelopment, neuroinflammation, and BBB development. The balance between Wnt-β-catenin and Shh pathways controls angiogenesis, barriergenesis, neurodevelopment, central nervous system (CNS) morphogenesis, and neuronal guidance. These interactions are critical to maintain BBB function in the mature CNS to prevent the influx of pathogens and inflammatory cells. Genetic mutations of key components of these pathways have been identified in ASD patients and animal models, which correlate with the severity of ASD symptoms. Disruption of the Shh/Wnt crosstalk may therefore compromise BBB development and function. In turn, impaired Shh signaling and glial activation may cause neuroinflammation that could disrupt the BBB. Elucidating how ASD-related mutations of Shh/Wnt signaling could cause BBB leaks and neuroinflammation will contribute to our understanding of the role of their interactions in ASD pathophysiology. These observations may provide novel targeted therapeutic strategies to prevent or alleviate ASD symptoms while preserving normal developmental processes.more » « less
-
Claesen, Jan (Ed.)ABSTRACT Atopic dermatitis (AD) is associated with a deficiency of skin lipids, increased populations of Staphylococcus aureus in the microbiome, and structural defects in the stratum corneum (SC), the outermost layer of human skin. However, the pathogenesis of AD is ambiguous, as it is unclear whether observed changes are the result of AD or contribute to the pathogenesis of the disease. Previous studies have shown that S. aureus is capable of permeating across isolated human SC tissue when lipids are depleted to levels consistent with AD conditions. In this study, we expand upon this discovery to determine the mechanisms and implications of bacterial penetration into the SC barrier. Specifically, we establish if bacteria are permeating intercellularly or employing a combination of both inter- and intracellular travel. The mechanical implications of bacterial invasion, lipid depletion, and media immersion are also evaluated using a newly developed, physiologically relevant, temperature-controlled drip chamber. Results reveal for the first time that S. aureus can be internalized by corneocytes, indicating transcellular movement through the tissue during permeation, consistent with previous theoretical models. S. aureus also degrades the mechanical integrity of human SC, particularly when the tissue is partially depleted of lipids. These observed mechanical changes are likely the cause of broken or ruptured tissue seen as exudative lesions in AD flares. This work further highlights the necessity of lipids in skin microbial barrier function. IMPORTANCE Millions of people suffer from the chronic inflammatory skin disease atopic dermatitis (AD), whose symptoms are associated with a deficiency of skin lipids that exhibit antimicrobial functions and increased populations of the opportunistic pathogen Staphylococcus aureus . However, the pathogenesis of AD is ambiguous, and it remains unclear if these observed changes are merely the result of AD or contribute to the pathogenesis of the disease. In this article, we demonstrate the necessity of skin lipids in preventing S. aureus from penetrating the outermost barrier of human skin, thereby causing a degradation in tissue integrity. This bacterial permeation into the viable epidermis could act as an inflammatory trigger of the disease. When coupled with delipidated AD tissue conditions, bacterial permeation can also explain increased tissue fragility, potentially causing lesion formation in AD patients that results in further enhancing bacterial permeability across the stratum corneum and the development of chronic conditions.more » « less
-
Microglia-mediated inflammation plays a significant role in neuronal and vascular damage in diabetic retinopathy (DR), but the mechanism linking inflammation, neurodegeneration, and impaired vascular integrity is still unclear. Previous studies from diabetic mouse models showed accumulation of fibrinogen at vessel lesions surrounded by perivascular microglial clusters. The purpose of this study was to evaluate whether the pathological hallmarks of gliosis and vascular aberrations characterized in diabetic animal models are consistent with those in diabetic human retinas, and to assess the effects of the defibrinogenating agent ancrod in retinal pathology and visual acuity in a two-hit inflammatory diabetic mouse model. Post-mortem human eyes were assessed for retinal and inflammatory gene expression by quantitative PCR. Immunohistochemical analyses in human and murine retinas were performed using markers of gliosis, vascular integrity, and fibrinogen deposition. An inflammatory microenvironment, with microgliosis and microaneurysms, was found in the diabetic human eye. Microglial activation, fibrinogen deposition, and axonal loss were also observed in the diabetic murine retina. Ancrod treatment correlated with reduced microgliosis, less fibrinogen deposition, and reduced pro-inflammatory cytokine levels in diseased retinal tissues. Together, these data suggest that fibrinogen contributes to microglia-mediated inflammation in the diabetic retina. Since retinal microgliosis, vascular pathology, and vision deficits manifest in diabetic mice irrespective of CX3CR1 genotype, our results indicate that defibrinogenation can dampen systemic neuroinflammation and vascular insults, thereby improving vision at early stages of diabetes. Summary Statement Diabetic human and murine retinas revealed pronounced microglial morphological activation and vascular abnormalities associated with inflammation. Pharmacological fibrinogen depletion using ancrod dampened microglial morphology alterations, resolved fibrinogen accumulation, rescued axonal integrity, and reduced inflammation in the diabetic murine retina.more » « less
