Mice exposed to World Trade Center dust exhibit a major impairment in spatial recognition and short- and long-term memory, in addition to changes in genes related to immune-inflammatory responses and blood-brain barrier disruption, in keeping with a study conducted by researchers from the Icahn School of Medicine at Mount Sinai and published January 17 within the Journal of Alzheimer’s Disease.
The study suggests a peripheral-brain immune inflammatory “cross-talking” that will increase the likelihood of cognitive decline, identifying key steps that could be therapeutically targetable in future studies of World Trade Center first responders.
“It’s imperative that we understand the danger for Alzheimer’s disease in aging first responders and other subjects exposed to Ground Zero in order that we will develop preventive initiatives,” said Giulio Maria Pasinetti, MD, PhD, the Saunders Family Professor of Neurology and Program Director for the Mount Sinai Center for Molecular Integrative Neuroresilience at Icahn Mount Sinai and senior writer of the paper.
The September 11, 2001, terrorist attacks on the World Trade Center led to intense fires, which produced an enormous, dense cloud of toxic gases and suspended pulverized debris comprising particles of various sizes that contained metals, polychlorinated biphenyls, and polyaromatic hydrocarbons, amongst other known toxins, collectively generally known as World Trade Center particulate matter (WTCPM).
Within the years following the attack and cleanup efforts, a cluster of chronic health conditions emerged amongst first responders who, working at Ground Zero for prolonged time periods, were repeatedly exposed to high levels of this particulate matter. Among the many chronic health conditions, a growing body of scientific literature indicates that these first responders could have a greater incidence of mild cognitive impairment, in addition to other neurological complications like changes in white matter connectivity and/or decreased hippocampal volume, which can put them at a greater risk of developing Alzheimer’s disease later in life.
Based on epidemiological and preliminary data, we hypothesized that first responders repeatedly exposed to Ground Zero dusts in the primary week post-disaster were placed at greater risk of age-related neurological conditions like Alzheimer’s disease and Alzheimer’s disease-related dementias attributable to changes in blood-brain barrier permeability, and/or neuro-immune interactions. Our study revealed that acute exposure to World Trade Center particulate matter may speed up cognitive deterioration and Alzheimer’s disease-type neuropathology in mice genetically modified to develop Alzheimer’s disease. And our transcriptomic evaluation strongly suggests that this exposure may trigger generalized immune inflammatory cascades which can underlie the collective pathophysiology being experienced by first responders.”
Ruth Iban-Arias, PhD, Postdoctoral Fellow, Department of Neurology, Icahn Mount Sinai
To check their hypothesis, researchers from the Center for Molecular Integrative Neuroresilience at Mount Sinai used mice genetically engineered to develop Alzheimer’s disease (5XFAD) and wild-type mice as controls. Mice within the treatment groups were exposed to repeated intranasal instillation of WTCPM dust-;which was collected at Ground Zero inside 72 hours after the attacks-;for 3 consecutive days for 3 weeks, reflecting the air level exposures faced by first responders at Ground Zero. The animals were exposed to WTCPM dust with high and low doses to discover a dose-dependent response.
Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Throughout the Y-maze assay, the mouse was placed initially of a Y-shaped maze and allowed to roam freely for 10 minutes. Generally, mice have an innate tendency to explore the environment they’ve not recently visited; spatial working memory impairment on this assay is defined as behavior wherein a mouse re-enters the identical arm(s) repeatedly, indicating that it doesn’t remember which arms it has already explored. Seven days later, mice were assessed via a novel recognition test, wherein each mouse was placed in an enclosure with two objects (a salt shaker and a toy block) and given 10 minutes to analyze. Time spent with each objects was recorded. Each mouse was removed and subsequently returned to the enclosure that contained a well-recognized object from the previous trial and a novel object. Cognitively intact mice display an innate tendency to spend a greater period of time investigating the novel object slightly than the familiar one. Thus, an animal that doesn’t remember which object it has been exposed to previously will spend similar amounts of time exploring each objects.
Each the control and 5XFAD mice exhibited a ten percent decrease in working memory after exposure to WTCPM dust, with only the high-exposure group displaying significant impairment in comparison with those not exposed to the dust. The 5XFAD mice exposed to high doses of dust and subjected to the Novel Object Recognition task showed a 16 percent and 30 percent (short- and long-term, respectively) increased preference to explore the familiar object slightly than the novel in comparison to no-exposure mice, depicting underlying memory alteration, evidently attributable to dust exposure.
The researchers also performed transcriptomic evaluation (study of the entire set of RNA transcripts which are produced within the genome) within the blood and hippocampus of each sets of mice.
Exposure to WTCPM dust evoked quite a lot of perturbations in immune function, cell signaling, and homeostatic functioning. Interestingly, a trending increase in neutrophils, the granulocytes of the innate immune system, was also noted within the peripheral blood of WTCPM-exposed 5XFAD mice, in comparison with 5XFAD mice exposed to saline solution containing no dust. Overall, significant activation of pathways with an overarching theme of inflammation including acute phase response signaling were upregulated.
WTCPM dust also exacerbated the neuroinflammatory profile within the mouse brain. The researchers found significant upregulation within the expression of genes involved in blood-brain barrier.
These effects are indicative of a peripherally mounted innate immune response, which could synergistically spread neuroinflammation. Results indicate that the exposure to WTCPM could have exerted peripheral immune responses, ultimately leading to the disruption of brain endothelial tight junction proteins and resulting in a permissive vascular permeability for the migration of peripheral immune modulators to the brain.
“While we must always cautiously interpret the outcomes of those preclinical studies and further investigation within the clinical setting is required, our study provides precious information relevant to the health of first responders. The info opens a recent horizon for investigations to further understand the impact that acute exposure to WTCPM dust has on the accelerated onset of Alzheimer’s and related dementias in first responders who at the moment are reaching older age,” said Dr. Pasinetti.
The Mount Sinai research team is currently conducting preclinical studies that explore the interaction between mice expressing the human type of APOE4/4 (the best genetic risk think about late-onset Alzheimer’s disease) and exposure to WTCPM dust to look at the possible accelerated onset of Alzheimer’s disease-type phenotype. These studies will provide the much-needed information for preventive screening and possibly interventions in first responders and other individuals who were exposed to the dust who’ve genetic susceptibility to Alzheimer’s disease.
Source:
Mount Sinai Health System