Dissecting Cellular Models and Tau Etiology in Gulf War Illness
Kendra L. Case
Advisors: Peter W. Baas, Anna Denise R. Garcia
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Abstract
A third of all United States veterans deployed in the first Gulf War (GW) have developed Gulf War Illness (GWI), a chronic multi-symptomatic disease affecting the musculoskeletal, gastrointestinal, and central nervous systems (CNS). The CNS symptoms include impairments in sleep attention/concentration, as well as learning and memory. GWI is hypothesized to arise due to a combination of wartimes stress and toxic exposures. Many studies on GWI have been restricted to animal models.
We have taken a cellular approach in which GWI-related toxicants are applied to either cultured rat hippocampal neurons or forebrain organoids derived from peripheral blood mononuclear cells donated from similarly deployed veterans with or without GWI. These three-dimensional multicellular structures resemble the human brain and provide the most human-like model to evaluate cellular changes that result from toxicant exposures.
Our results on the organoids, which align with previous studies with cortisol (to mimic stress) coupled with an organophosphate (diisopropyl fluorophosphate), point to tau pathology as a key driver of GWI. However, there are multiple GWI toxicant regimens used in different laboratories but no detailed studies of different effects of these regimens or what can be learned by comparing them.
To rectify that gap in knowledge, we used primary rat hippocampal neuron cultures to compare two relevant GWI toxicant treatments: the OP regimen used in our organoid studies and a commonly used Non-Organophosphate (Non-OP) regimen. We used rat, with corticosterone to mimic stress, so that our results could be correlated with previous and future histological and behavioral studies relevant to therapy.
Both toxicant regimens converged on tau pathology, with corresponding changes in microtubules and synapses, albeit with somewhat different changes, suggesting that particular features of tau pathology might define the particular constellation of symptoms associated with different toxicant exposures.
Defining GWI as a tauopathy and launching investigations into tau as a therapeutic target may bring treatment to these veterans on an accelerated timeline, which is urgent, given the potential for a prolonged early phase tauopathy to escalate into dementia.
Web | DOI | Drexel University | Thesis | Open Access
Kendra L. Case
Advisors: Peter W. Baas, Anna Denise R. Garcia
[Line breaks added]
Abstract
A third of all United States veterans deployed in the first Gulf War (GW) have developed Gulf War Illness (GWI), a chronic multi-symptomatic disease affecting the musculoskeletal, gastrointestinal, and central nervous systems (CNS). The CNS symptoms include impairments in sleep attention/concentration, as well as learning and memory. GWI is hypothesized to arise due to a combination of wartimes stress and toxic exposures. Many studies on GWI have been restricted to animal models.
We have taken a cellular approach in which GWI-related toxicants are applied to either cultured rat hippocampal neurons or forebrain organoids derived from peripheral blood mononuclear cells donated from similarly deployed veterans with or without GWI. These three-dimensional multicellular structures resemble the human brain and provide the most human-like model to evaluate cellular changes that result from toxicant exposures.
Our results on the organoids, which align with previous studies with cortisol (to mimic stress) coupled with an organophosphate (diisopropyl fluorophosphate), point to tau pathology as a key driver of GWI. However, there are multiple GWI toxicant regimens used in different laboratories but no detailed studies of different effects of these regimens or what can be learned by comparing them.
To rectify that gap in knowledge, we used primary rat hippocampal neuron cultures to compare two relevant GWI toxicant treatments: the OP regimen used in our organoid studies and a commonly used Non-Organophosphate (Non-OP) regimen. We used rat, with corticosterone to mimic stress, so that our results could be correlated with previous and future histological and behavioral studies relevant to therapy.
Both toxicant regimens converged on tau pathology, with corresponding changes in microtubules and synapses, albeit with somewhat different changes, suggesting that particular features of tau pathology might define the particular constellation of symptoms associated with different toxicant exposures.
Defining GWI as a tauopathy and launching investigations into tau as a therapeutic target may bring treatment to these veterans on an accelerated timeline, which is urgent, given the potential for a prolonged early phase tauopathy to escalate into dementia.
Web | DOI | Drexel University | Thesis | Open Access
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