Mice exposed to World Trade Center dust not only show significant impairments in spatial perception and short- and long-term memory, but also genetic alterations associated with immune-inflammatory responses and blood-brain barrier disruption. Published on his January 17th at the Icahn School of Medicine, Mount Sinai. Alzheimer’s Journal.
This study suggests that immune-inflammatory ‘crosstalk’ in the peripheral brain may increase the likelihood of cognitive decline and could be targeted for treatment in future studies of first responders at the World Trade Center. We have identified important steps that could
“It’s imperative to understand the risk of Alzheimer’s disease in aging first responders and other subjects exposed to ground zero so that prevention initiatives can be developed,” said Sanders Family Professor of Neurology and program director. said Giulio Maria Pasinetti, M.D. Senior author of the Mount Sinai Center and dissertation for his Molecular Integrative Neuroresilience at Icahn Mount Sinai.
The terrorist attacks on the World Trade Center on September 11, 2001 caused violent fires, creating huge, dense clouds of toxic gases and particles of various sizes, including metals, polychlorinated biphenyls and polyaromatic hydrocarbons. Powdery debris consisting of was floating. Known toxins collectively known as World Trade Center Particulate Matter (WTCPM).
In the years following the attack and cleanup efforts, clusters of chronic health conditions developed among first responders who worked long hours at Ground Zero and were repeatedly exposed to high levels of this particulate matter. A growing body of scientific literature indicates that among chronic health conditions, these first responders may have an increased incidence of mild cognitive impairment, including changes in white matter connectivity and hippocampal volume. There may also be other neurological complications such as reduction. Increased risk of developing Alzheimer’s disease later in life.
Based on epidemiological and preliminary data, first responders who were repeatedly exposed to ground zero dust in the first week after the disaster were more likely to develop complications such as Alzheimer’s disease due to blood changes and Alzheimer’s disease-related dementia. We hypothesized that there would be an increased risk of age-related neurological conditions. – Brain barrier permeability, and/or neuroimmune interactions. Our study shows that acute exposure to World Trade Center particulate matter may accelerate cognitive decline and Alzheimer’s-type neuropathology in mice genetically engineered to develop Alzheimer’s disease. made it clear. And our transcriptome analysis suggests that this exposure may trigger a systemic immune-inflammatory cascade that may underlie the collective pathophysiology experienced by first responders. strongly suggests.
Ruth Iban-Arias, PhD, Postdoctoral Fellow, Department of Neurology, Icahn Mount Sinai
To test their hypothesis, researchers at Mount Sinai’s Center for Molecular Integration and Neurorestoration used mice genetically engineered to develop Alzheimer’s disease (5XFAD) and wild-type mice as controls. Mice in the treatment group were exposed to an intranasal injection of her WTCPM dust collected at ground zero within 72 hours after challenge for 3 consecutive days for 3 weeks. Animals were exposed to high and low doses of her WTCPM dust to confirm a dose-dependent response.
A Y-maze assay and a novel object recognition behavioral test were performed for working memory impairment and learning and recognition memory, respectively. During the Y-maze assay, mice were placed at the starting point of the Y-maze and allowed to roam freely for 10 min. In general, mice have an innate tendency to explore environments they have not visited recently. Spatial working memory impairment in this assay is defined as the behavior of mice repeatedly re-entering the same arm, indicating that they do not remember already explored arms. After 7 days, mice were evaluated by a novel cognitive test. In this test, each mouse was placed in an enclosure containing her two objects (a salt shaker and a toy block) and investigated for 10 minutes. Time spent on both objects was recorded. Each mouse was removed and then returned to its enclosure containing familiar and new objects from previous trials. Cognitively intact mice show an innate tendency to spend more time investigating novel objects than familiar ones. Therefore, animals that do not remember previously exposed objects spend an equal amount of time exploring both objects.
Both control and 5XFAD mice had a 10% decrease in working memory after exposure to WTCPM dust. 5XFAD mice exposed to high doses of dust and subjected to novel object recognition tasks were 16% and 30% more likely to explore familiar objects than novel objects, respectively (short-term and long-term ) showed that it increased. Exposed mice clearly show alterations in underlying memory due to dust exposure.
The researchers also performed transcriptome analysis (the study of the complete set of RNA transcripts produced in the genome) in the blood and hippocampus of both mice.
Exposure to WTCPM dust caused various perturbations in immune function, cell signaling and homeostatic function. Interestingly, an increased propensity for neutrophils, granulocytes of the innate immune system, was also observed in the peripheral blood of WTCPM-exposed 5XFAD mice compared to dust-free saline-exposed 5XFAD mice. Approved. Overall, significant activation of pathways with the overarching theme of inflammation was upregulated, including acute phase response signaling.
WTCPM dust also exacerbated the neuroinflammatory profile in the mouse brain. Researchers found that the expression of genes involved in the blood-brain barrier was significantly upregulated.
These effects indicate a peripherally mounted innate immune response that may synergistically spread neuroinflammation. The results suggest that exposure to WTCPM exerts a peripheral immune response, ultimately leading to disruption of brain endothelial tight junction proteins, which may result in permissive vascular permeability for the migration of peripheral immune regulators into the brain. It shows that there is
“While the results of these preclinical studies need to be interpreted with caution and require further investigation in the clinical setting, our study provides valuable information relevant to the health of first responders. The data open new horizons of investigation to further understand acute effects. said Dr. Pasinetti.
The researchers at Mount Sinai are currently conducting preclinical studies looking at interactions between humanoid mice. APOE4/4 (highest genetic risk factor in late-onset Alzheimer’s disease) and exposure to WTCPM dust to examine the possibility of accelerated onset of Alzheimer’s disease-type phenotypes. These studies provide the information needed for preventative screening and possibly intervention for first responders and other dust-exposed individuals with genetic susceptibility to Alzheimer’s disease.
Mount Sinai Health System