High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer’s Disease Mutations

AUTHORS

Robert G. Hinshaw, Maren K. Schroeder, Jason Ciola, Curran Varma, Brianna Colletti, Bin Liu, Grace Geyu Liu, Qiaoqiao Shi, Jacqueline P. Williams, M. Kerry O’Banion, Barbara J. Caldarone and Cynthia A. Lemere

ABSTRACT

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer’s-like and wildtype littermate mice 7–8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer’s model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.

Increased Toll-like Receptor-MyD88-NFκB-Proinflammatory neuroimmune signaling in the orbitofrontal cortex of humans with alcohol use disorder

AUTHORS

Ryan P. Vetreno, Liya Qin, Leon G. Coleman Jr, Fulton T. Crews

ABSTRACT

Background: Many brain disorders, including alcohol use disorder (AUD), are associated with induction of multiple proinflammatory genes. One aspect of proinflammatory signaling is progressive increases in expression across cells and induction of other innate immune genes. High-mobility group box 1 (HMGB1) heteromers contribute to amplification by potentiating multiple proinflammatory responses, including Tolllike receptors (TLRs). TLR signaling recruits coupling proteins linked to nuclear transcription factors that induce proinflammatory cytokines and chemokines and their respective receptors. We tested the hypothesis that AUD induction of TLR expression increases levels of proinflammatory genes and cellular signaling cascades in association with neurodegeneration in the orbitofrontal cortex (OFC).

Methods: Postmortem human OFC tissue samples (n = 10) from males diagnosed with

AUD were compared to age-matched moderate drinking controls (CON). Neuroimmune

signaling molecules were assessed using immunohistochemistry for protein and reverse transcription polymerase chain reaction for messenger RNA (mRNA).

Results: In the AUD OFC, we report induction of the endogenous TLR agonist HMGB1as well as all TLRs assessed (i.e., TLR2-TLR9) except TLR1. This was accompanied by increased expression of the TLR adaptor protein myeloid differentiation primary response 88 (MyD88), activation of the proinflammatory nuclear transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and downstream induction of proinflammatory cytokines, chemokines, and their corresponding receptors. Several of these proinflammatory signaling markers are expressed in glia and neurons. The induction of HMGB1-TLR-MyD88-NFκB proinflammatory signaling pathways correlates with neurodegeneration (i.e., Fluoro-Jade B), lifetime alcohol consumption, and age of drinking onset.

Conclusion: These data implicate the induction of HMGB1-TLR-MyD88-NFκB cascades through coordinated glial and neuronal signaling as contributors to the neurodegeneration seen in the postmortem human OFC of individuals with AUD