summary: Mice exposed to WTC dust showed impairments in both long- and short-term memory, and spatial recognition, as well as alterations in genes associated with the inflammatory immune response and blood-brain barrier dysfunction. The results indicate that first responders exposed to dust from the World Trade Center experience a peripheral brain immune inflammatory response that leads to cognitive decline.
Source: Mount Sinai Hospital
Mice exposed to WTC dust showed significant impairments in spatial recognition, short- and long-term memory, as well as alterations in genes related to immune inflammatory responses and disruption of the blood-brain barrier, according to a study led by researchers from the Icahn School of Medicine at Mount Sinai and published Jan. 17 in the issue. Alzheimer’s Disease Journal.
The study suggests the existence of a peripheral brain immune-inflammatory ‘crosstalk’ that may increase the potential for cognitive decline, and identifies key steps that may be therapeutically targetable in future studies of WTC first responders.
“It is essential that we understand the risk of Alzheimer’s disease in geriatric first responders and others exposed to Ground Zero so that we can develop preventive initiatives,” Giulio Maria Pasinetti, MD, PhD, professor of neurology and program director for the Mount Sinai Center, told the Mount Sinai Center. For Molecular Integrative Neurotherapy at Icahn-Mount-Sinai and senior author of the paper.
The terrorist attacks of September 11, 2001 on the World Trade Center led to intense fires, creating a huge and dense cloud of toxic gases and flying suspended debris consisting of particles of various sizes containing metals, PCBs and polycyclic hydrocarbons, among others. other. Known toxins, collectively known as World Trade Center Particulate matter (WTCPM).
In the years following the attack and the cleanup effort, a host of chronic health conditions developed among the first responders who worked at Ground Zero for extended periods, and were repeatedly exposed to high levels of these particles.
Among chronic health conditions, a growing body of scientific literature suggests that these first responders may have a greater rate of mild cognitive impairment, as well as other neurological complications such as changes in white matter connectivity and/or decreased hippocampal volume, which may put them at greater risk. to Alzheimer’s disease later in life.
“Based on epidemiological and preliminary data, we hypothesized that first responders who were repeatedly exposed to Ground Zero dust in the first week after the disaster had an increased risk of developing age-related neurological conditions such as Alzheimer’s disease and Alzheimer’s-related dementia due to changes in Postdoc in the Department of Neurology at Icahn-Mount Sinai: “Blood-brain barrier permeability, and/or neuroimmune interactions.”
Our study revealed that acute exposure to particulate matter in WTC may accelerate cognitive decline and Alzheimer’s-type neuropathology in mice genetically engineered to develop Alzheimer’s disease. Our transcriptomic analysis strongly suggests that such exposure may induce generalized immune-inflammatory cascades that may underlie the collective pathophysiology experienced by first responders. “
To test their hypothesis, researchers from the Center for Molecular Integrative Neuronal Resistance at Mount Sinai used mice genetically engineered to develop Alzheimer’s disease (5XFAD) and wild-type mice as controls.
Rats in the treatment groups were subjected to repeated nasal instillation of WTCPM dust – collected at Ground Zero within 72 hours after the attacks – on three consecutive days for three weeks, reflecting the level of air exposure encountered by the first responders at Ground Zero.
Animals were exposed to WTCPM dust at high and low doses to determine a dose-dependent response.
The Y-maze and novel object recognition behavioral tests were performed for the working memory, learning and recognition memory deficits, respectively. During the Y-maze test, the mouse was placed at the beginning of a Y-shaped maze and allowed to roam freely for 10 minutes.
In general, rats have an innate tendency to explore an environment they haven’t visited recently; Spatial working memory impairment is defined in this test as a behavior where the mouse re-enters the same arm(s) repeatedly, indicating that it does not remember which arms it has already detected.
Seven days later, the rats were assessed with the novel recognition test, in which each rat was placed in a container with two objects (a salt shaker and a toy block) and given 10 minutes to investigate. The time elapsed with both objects was recorded.
Each rat was removed and then returned to the enclosure containing a familiar object from the previous experiment and a new object. Cognitively healthy mice display an innate tendency to spend a greater amount of time investigating the new object rather than the familiar object.
Thus, an animal that does not remember the object it was previously exposed to will spend a similar amount of time exploring both objects.
Both control mice and 5XFAD mice showed a 10 percent decrease in working memory after exposure to WTCPM dust, with only the higher exposure group showing significant impairment compared to those not exposed to the dust.
5XFAD rats exposed to high doses of dust and subjected to the novel object recognition task showed a 16% and 30% increased preference (in the short and long term, respectively) to explore the familiar rather than the novel object when compared to no-exposure rats, which depict an altered memory Primary, obviously due to exposure to dust.
The researchers also performed a transcriptomic analysis (the study of the complete set of RNA transcripts that are produced in the genome) in the blood and hippocampus of both groups of mice.
Exposure to WTCPM dust triggered a variety of perturbations in immune function, cell signaling, and homeostatic performance. Interestingly, a common increase in neutrophils, granulocytes of the innate immune system, was also observed in the peripheral blood of 5XFAD mice exposed to WTCPM, compared to 5XFAD mice exposed to saline without dust. Overall, significant activation of pathways with an overall theme of inflammation including acute phase response signaling was upregulated.
WTCPM dust also exacerbated the neuroinflammatory profile in mouse brain. The researchers found a significant upregulation in the expression of genes involved in the blood-brain barrier.
These effects are indicative of a peripheral innate immune response, which may synergistically propagate neuroinflammations.
The results suggest that exposure to WTCPM may have induced peripheral immune responses, ultimately leading to disruption of brain endothelial tight junction proteins and leading to permissive vascular permeability for migration of peripheral immune systems into the brain.
“While we must interpret the results of these preclinical studies with caution and further investigation is needed in the clinical setting, our study provides valuable information relevant to the health of first responders.
“The data opens a new avenue for investigations to understand the impact of acute exposure to WTCPM dust on precipitating the onset of Alzheimer’s disease and related dementia in first responders who are now older,” said Dr. Pasinetti.
The Mount Sinai research team is currently conducting preclinical studies to explore the interaction between mice expressing the human form of APOE4/4 (highest genetic risk factor for late-onset Alzheimer’s disease) and exposure to WTCPM dust to examine the possible accelerated onset of the Alzheimer’s disease phenotype.
These studies will provide much-needed information for preventive screening and possibly interventions in first responders and other individuals who have been exposed to dust and have a genetic susceptibility to Alzheimer’s disease.
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author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
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“Exposure to WTC dust exacerbates cognitive impairment and elicits a central and peripheral transcriptional profile of inflammation in an animal model of Alzheimer’s disease.Written by Giulio Maria Pacinetti, et al. Alzheimer’s Disease Journal
Exposure to WTC dust exacerbates cognitive impairment and elicits a central and peripheral transcriptional profile of inflammation in an animal model of Alzheimer’s disease.
The terrorist attacks of September 11, 2001 on the World Trade Center (WTC) resulted in massive fires, a huge dense cloud of toxic gases, and suspended debris. In subsequent years, after the attack and cleanup efforts, a range of chronic health conditions developed among First Responders (FR) who had been at Ground Zero for extended periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among these are neurological complications that may increase the risk of developing Alzheimer’s disease (AD) later in life.
We hypothesize that exposure to WTCPM dust affects immunological crosstalk between the peripheral and central nervous systems that may induce brain permeability ultimately promoting the AD-type phenotype.
5XFAD mice and wild-type mice were administered intranasally using WTCPM dust collected at Ground Zero within 72 hours after the attacks. The Y-maze and novel object recognition behavioral tests were performed for the working memory, learning and recognition memory deficits, respectively. Transcriptome analysis was performed in blood and hippocampus and confirmed by RT qPCR.
Mice exposed to WTCPM dust showed significant impairment in short- and long-term spatial and cognitive memory. Furthermore, transcriptome analysis in hippocampal and hematopoietic composition revealed significant alterations in genes related to immune inflammatory responses, and blood-brain barrier disruption.
These studies point to a putative talk of brain peripheral immune inflammation that may induce cognitive decline, and identify for the first time key steps that may be therapeutically targetable in future studies in the WTC-F.