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Background: The September 11, 2001, catastrophe unleashed widespread destruction beyond the World Center (WTC), with fires and toxic gases leaving lasting impacts. First responders at Ground Zero faced prolonged exposure to hazardous particulate matter (PM), resulting in chronic health challenges. Among the multitude of health concerns, the potential association between the WTCPM and Alzheimer's disease (AD) has emerged as an area of intense inquiry, probing the intricate interplay between environmental factors and neurodegenerative diseases. Objective: We posit that a genetic predisposition to AD in mice results in dysregulation of the gut-brain axis following chronic exposure to WTCPM. This, in turn, may heighten the risk of AD-like symptoms in these individuals. Methods: 3xTg-AD and WT mice were intranasally administered with WTCPM collected at Ground Zero within 72âhours after the attacks. Working memory and learning and recognition memory were monitored for 4 months. Moreover, brain transcriptomic analysis and gut barrier permeability along with microbiome composition were examined. Results: Our findings underscore the deleterious effects of WTCPM on cognitive function, as well as notable alterations in brain genes associated with synaptic plasticity, pro-survival, and inflammatory signaling pathways. Complementary, chronic exposure to the WTCPM led to increased gut permeability in AD mice and altered bacteria composition and expression of functional pathways in the gut. Conclusions: Our results hint at a complex interplay between gut and brain axis, suggesting potential mechanisms through which WTCPM exposure may exacerbate cognitive decline. Identifying these pathways offers opportunities for tailored interventions to alleviate neurological effects among first responders.
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Immune system dysfunction is increasingly recognized as a significant feature that contributes to Alzheimer's disease (AD) pathogenesis, reflected by alterations in central and peripheral responses leading to detrimental mechanisms that can contribute to the worsening of the disease. The damaging alterations in the peripheral immune system may disrupt the peripheral-central immune crosstalk, implicating the gut microbiota in this complex interaction. The central hypothesis posits that the immune signature inherently harbored in bone marrow (BM) cells can be transferred through allogeneic transplantation, influencing the recipient's immune system and modulating peripheral, gut, and brain immune responses. Employing a genetically modified mouse model to develop AD-type pathology we found that recipient wild-type (WT) mice engrafted with AD-derived BM, recapitulated the peripheral immune inflammatory donor phenotype, associated with a significant acceleration of cognitive deterioration in the absence of any overt change in AD-type amyloid neuropathology. Moreover, transcriptomic and phylogenetic 16S microbiome analysis evidence on these animals revealed a significantly impaired expression of genes associated with synaptic plasticity and neurotransmission in the brain and reduced bacteria diversity, respectively, compared to mice engrafted with WT BM. This investigation sheds light on the pivotal role of the peripheral immune system in the brain-gut-periphery axis and its profound potential to shape the trajectory of AD. In summary, this study advances our understanding of the complex interplay among the peripheral immune system, brain functionality, and the gut microbiome, which collectively influence AD onset and progression.
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Doença de Alzheimer , Microbioma Gastrointestinal , Doenças do Sistema Nervoso , Camundongos , Animais , Doença de Alzheimer/patologia , Microbioma Gastrointestinal/fisiologia , Transplante de Medula Óssea , Filogenia , Fenótipo , Plasticidade Neuronal , Camundongos TransgênicosRESUMO
Forkhead box P3 (Foxp3) is a transcription factor that influences functioning of regulatory T cells (Tregs) that modulate peripheral immune response. Treg-mediated innate immunity and Treg-mediated adaptive immunity are receiving considerable attention for their implication in mechanisms associated with anxiety and depression. Here, we demonstrated that depletion of Foxp3-expressing cells causally promotes transient anxiety- and depression-like behaviors associated with inflammasome activation in "depletion of regulatory T cell" (DEREG) mice. We found that restoration of Foxp3-expressing cells causally reverses neurobehavioral changes through alteration of innate immune responses as assessed by caspase-1 activity and interleukin-1ß (IL-1ß) release in the hippocampal formation of DEREG mice. Moreover, we found that depletion of Foxp3-expressing cells induces a significant elevation of granulocytes, monocytes, and macrophages in the blood, which are associated with transient expression of the matrix metalloprotease-9. Similarly, we found that depletion of Foxp3-expressing cells in 5xFAD, a mouse model of Alzheimer's disease (AD), exhibits elevated activated caspase-1 and promotion of IL-1ß secretion and increased the level of amyloid-beta (Aß)1-42 and Aß plaque burden in the hippocampal formation that coincided with an acceleration of cognitive decline at a presymptomatic age in the 5xFAD mice. Thus, our study provides evidence supporting the idea that Foxp3 may have a causal influence on peripheral immune responses. This, in turn, can promote an innate immune response within the brain, potentially leading to anxiety- and depression-like behaviors or cognitive decline.
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Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition in some patients with post-acute sequelae of SARS-CoV-2 (PASC). To evaluate neuropathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Brodmann area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer's disease (AD), and SARS-CoV-2-infected AD individuals compared to age- and gender-matched neurological cases. Here, we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2-infected AD individuals. Distribution of microglial changes reflected by the increase in Iba-1 reveals nodular morphological alterations in SARS-CoV-2-infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help in informing decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD.
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Doença de Alzheimer , COVID-19 , Humanos , SARS-CoV-2 , Barreira Hematoencefálica , Cognição , Progressão da DoençaRESUMO
BACKGROUND: The terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer's disease (AD) later in life. OBJECTIVE: We hypothesize that WTCPM dust exposure affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype. METHODS: 5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72âh after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR. RESULTS: Mice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption. CONCLUSION: These studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR.
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Doença de Alzheimer , Disfunção Cognitiva , Ataques Terroristas de 11 de Setembro , Camundongos , Animais , Poeira/análise , Doença de Alzheimer/genética , Modelos Animais , Disfunção Cognitiva/genéticaRESUMO
Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer's disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD. Teaser: SARS-CoV-2 and Alzheimer's disease share similar neuroinflammatory processes, which may help explain neuro-PASC.
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ABSTRACT: From January 2014 to December 2015, the overall yield of sexually transmitted infections testing among asymptomatic MSM was two-fold higher at a community-based versus clinic-based service. Compared with the clinic-based service, yield of chlamydia (9.0% vs 4.9%; P = 0.010), gonorrhea (6.5% vs 3.1%; P < 0.001), and infectious syphilis (0.9% vs 0.1%; P = 0.024) were all higher at the community-based service.
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Infecções por Chlamydia , Gonorreia , Infecções por HIV , Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Austrália/epidemiologia , Infecções por Chlamydia/diagnóstico , Infecções por Chlamydia/epidemiologia , Serviços de Saúde Comunitária , Gonorreia/diagnóstico , Gonorreia/epidemiologia , Homossexualidade Masculina , Humanos , Masculino , Parceiros Sexuais , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologiaRESUMO
People from culturally and linguistically diverse backgrounds, including low- and middle-income countries, account for a third of new HIV diagnoses in Australia and are a priority for HIV prevention and treatment programs. We describe the demographic and clinical characteristics of participants in the Australian HIV Observational Database (AHOD) and compare disease outcomes, progression to AIDS and treatment outcomes of those born in low- and middle-income countries, with those born in high-income countries and Australia. All participants enrolled in AHOD sites where country of birth is routinely collected were included in the study. Age, CD4 count, HIV viral load, antiretroviral therapy, hepatitis co-infection, all-cause mortality and AIDS illness were analysed. Of 2403 eligible participants, 77.3% were Australian born, 13.7% born in high-income countries and 9.0% born in middle- or low-income countries. Those born in Australia or high-income countries were more likely to be male (96%) than those from middle- or low-income countries (76%), p < .0001 and more likely to have acquired HIV via male to male sexual contact (77%; 79%) compared with those from middle- or low-income countries (50%), p < .0001. At enrolment, mean CD4 cell count was higher in Australian born (528 cells/µL) than both those born in high-income countries (468 cells/µL) and those born in middle- and low-income countries (451 cells/µL), p < .0001; whereas the mean HIV RNA level (log10 copies/mL) was similar in all three groups (4.44, 4.76 and 4.26, respectively), p = .19.There was no difference in adjusted incidence risk ratios for all-cause mortality and AIDS incidence in all three groups, p = .39. These findings reflect successful outcomes of people born in low- and middle-income countries once engaged in HIV care.