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A three-dimensional graphic design representation of the potential role of meningeal vessels in Alzheimer disease. Although there are major differences between APOE4(+) and APOE4(−) Alzheimer disease cases (described in detail in the Comment article by Mentis and colleagues), the figure depicts the clearance of macromolecules and other solutes from meningeal lymphatic vessels. Cover image: Ella Maru Studio.

Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in a male APPPS1-21 AD mouse model. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (ABX) and identified a significant increase in plasma propionate, a gut-derived short-chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the ABX-induced phenotype. Astrocyte-specific RNA-Seq on ABX- and propionate-treated mice showed reduced expression of proinflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments, in which we found that ABX and propionate decreased peripheral RAR-related orphan receptor-γ+ (Rorγt+) CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Last, using an IL-17 mAb to deplete IL-17, we found that propionate reduced reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for the treatment of AD.

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8 +  T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8 +  T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8 +  T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people.

Background: Idiopathic juvenile osteoporosis (IJO) is a rare condition characterized by low bone mass that can increase the risk of fractures in children. Treatment options for these patients are limited as the molecular mechanisms of disease initiation and progression are incompletely understood. Sclerostin inhibits canonical Wnt signaling, which is important for the bone formation activity of osteoblasts, and elevated sclerostin has been implicated in adult osteoporosis. Objective: To evaluate the role of sclerostin in IJO, high-resolution confocal microscopy analyses were performed on bone biopsies collected from 13 pediatric patients. Methods: Bone biopsies were stained with sclerostin, and β-catenin antibodies showed elevated expression across osteocytes and increased sclerostin-positive osteocytes in 8 of the 13 total IJO patients (62%). Results: Skeletal sclerostin was associated with static and dynamic histomorphometric parameters. Further, colocalization analyses showed that bone sclerostin colocalized with phosphorylated β-catenin, a hallmark of Wnt signaling that indicates Wnt inhibition. In contrast, sclerostin-positive osteocytes were not colocalized with an “active” unphosphorylated form of β-catenin. Conclusions: These results support a model that altered levels of sclerostin and Wnt signaling activity occur in IJO patients.

Our group has developed and validated an advanced microfluidic platform to improve preclinical modeling of healthy and disease states, enabling extended culture and detailed analysis of tissue-engineered miniaturized organ constructs, or “organs-on-chips.” Within this system, diverse cell types self-organize into perfused microvascular networks under dynamic flow within tissue chambers, effectively mimicking the structure and function of native tissues. This setup facilitates physiological intravascular delivery of nutrients, immune cells, and therapeutic agents, and creates a realistic microenvironment to study cellular interactions and tissue responses. Known as the vascularized micro-organ (VMO), this adaptable platform can be customized to represent various organ systems or tumors, forming a vascularized micro-tumor (VMT) for cancer studies. The VMO/VMT system closely simulates in vivo nutrient exchange and drug delivery within a 3D microenvironment, establishing a high-fidelity model for drug screening and mechanistic studies in vascular biology, cancer, and organ-specific pathologies. Furthermore, the optical transparency of the device supports high-resolution, real-time imaging of fluorescently labeled cells and molecules within the tissue construct, providing key insights into drug responses, cell interactions, and dynamic processes such as epithelial-mesenchymal transition. To manage the extensive imaging data generated, we created standardized, high-throughput workflows for image analysis. This manuscript presents our image processing and analysis pipeline, utilizing a suite of tools in Fiji/ImageJ to streamline data extraction from the VMO/VMT model, substantially reducing manual processing time. Additionally, we demonstrate how these tools can be adapted for analyzing imaging data from traditional in vitro models and microphysiological systems developed by other researchers.

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.

Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and АВ plaque accumulation in a male APPPS1-21 AD mouse model. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces AВ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (ABX) and identified a significant increase in plasma propionate, a gut-derived short-chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and АВ plaques in APPPS1-21 mice, phenocopying the ABX-induced phenotype. Astrocyte-specific RNA-Seq on ABX- and propionate-treated mice showed reduced expression of proinflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments, in which we found that ABX and propionate decreased peripheral RAR-related orphan receptor-y· (Roryt·) CD4· (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Last, using ап IL-17 mAb to deplete IL-17, we found that propionate reduced reactive astrocytosis and AВ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and АВ amyloidosis by decreasing peripheral Th17 cells and 11-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for the treatment of AD.

History tells us that post-pandemic worlds (e.g., after the second pandemic of plague in the 14th century and the 1918 influenza pandemic) were dramatically altered in almost every conceivable way, from human biology and demography to politics, economics, and religion. The reality that we left at the beginning of 2020 can no longer be restored.In discussions throughout our-tenure as the AJPH 2021 Student ThinkTank cohort, we found ourselves contemplating what it might mean to \"return to normal\" once the COVID-19 pandemic is over. Two viewpoints became apparent: (1) normal, as a construct, is relative to individuals or groups, and (2) the prepandemic normal as an indicator of equity was not working for everyone. Exacerbations of health and economic inequalities glared as the pandemic disrupted our lives. Disenfranchised people, such as those with disabilities, people of color, those residing in low-to middle-income households, and those with chronic illnesses, found themselves at the crosshairs of COVID-19, a stressed health care system, and economic shock. Perhaps conceptualizations of what we previously deemed as \"normal\" need to be challenged given that, in the practice of public health policy and leadership, realities are not static; normal is a fluid state in constant change as opposed to something to which we can collectively return.

Traumatic brain injury (TBI) afflicts about 69 million people worldwide yearly. Patients aged 65 years and older account for an increasing proportion of those who suffer from TBI. Aged TBI patients experience increased morbidity and mortality compared to young TBI patients. Understanding the disparate response between older and young patients after TBI is still in its infancy. Using a well-established mouse model of TBI, I have uncovered potential cellular culprits for worse TBI outcomes in aged mice – the disproportionate number of CD8 T-cells within aged brains after TBI. These T-cells come from the peripheral blood and infiltrate the brain as the blood-brain barrier (BBB) is damaged after TBI. Inhibiting the infiltration of these CD8 T-cells via an FDA-approved drug called Natalizumab (a monoclonal antibody against the adhesion molecule integrin α4), also known as anti-CD49d antibody (aCD49d Ab), significantly reduces mortality in the aged mice but not young mice post-TBI. This treatment also improves long-term neurocognition and motor outcomes in aged mice post-TBI. At the molecular level, mice incur age-associated toxic and heightened cytokine responses, as shown in numerous upregulated pro-inflammatory cytokines, long-term post-TBI. aCD49d Ab attenuates this response along with augmentation of a neuroprotective Th2 response. Furthermore, aged mouse brains post-TBI comprise two pools of CD8+ T cells on the basis of their effector function: a dysfunctional population, which co-expresses inhibitory receptors and markers for effector function, and a functional population, which exhibits markers for effector function. Attenuating the functional population, aCD49d Ab remediates the cytotoxicity of CD8+ T cells, improving post-TBI outcomes in aged mice. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in aged individuals.