Stress-Induced Alterations of Immune Profile in Animals Suffering by Tau Protein-Driven Neurodegeneration

Abstract

Alzheimer's disease (AD) is a multifactorial disorder; neurofibrillary pathology composed of tau protein is found side by side with amyloid-β deposits and extensive neuroinflammation. The immune system of the brain is considered as one of the factors that could influence the speed of the progression of AD neuropathology as a potential mediator of the damage induced by AD protein deposits. Alzheimer's disease pathology can be impacted by psychological stress; however, signalling pathways in background are not well known. We have explored possible avenues of how stress could influence the brain's immune system in a rat model of AD. Animals were subjected either to a single or multiple instances of immobilization stress. The analysis of a panel of immunity-related genes was used to evaluate the impact of stress on the immune response in the brain. We have identified 19 stress-responsive genes that are involved in neuroinflammation accompanying tau pathology: Nos2, Ptgs2, IL-8rb, C5, Mmp9, Cx3cr1, CD40lg, Adrb2, IL-6, IL-6r, IL-1r2, Ccl2, Ccl3, Ccl4, Ccl12, TNF-α, IL-1α, IL-1β, IL-10. Most of them are deregulated under the stress conditions also in control animals; however, the magnitude of the response to either acute or chronic stress differs. This can lead to serious influence, most probably to acceleration of neurodegenerative phenotype in diseased animals. Several of the genes (IL-1β, Casp1, Cx3cr1 and C5) are deregulated solely in tauopathic animals. The stress-induced changes in the inflammatory picture of the brain highlight the fact that the brain's immune response is highly responsive to environmental stimuli. The pattern of changes is indicative of an attempt to protect the brain in the short term, while being potentially detrimental to the response against a long-term pathological process such as neurofibrillary degeneration.

Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective

“…Specifically, the primary roles of IL-6 are largely coupled with the regulation of the other two proinflammatory cytokines IL-1β and TNF-α, and studies have reported that IL-6 often inhibits the expression of IL-1β and TNF-α while promoting IL-10 [90]. This has been suggested to be especially so when in an anti-inflammatory environment, where the integrity of the blood-brain barrier needs to be regulated [91], such as during the occurrence of neuroinflammatory responses.…”

An epigenome-wide association study of early-onset major depression in monozygotic twins

“…The MHC also is densely populated with genes related to neuronal signaling and plays a role in immunity. Other genes related to immune functioning (e.g., CX3CR1 , IL23R ) 100 – 103 also emerged. Study results support multiple etiologic pathways to MD and indicate that complex genetic disorders such as MD likely reflect a large number of independent genetic factors that each contribute a small amount of variance to disease susceptibility and multiple psychiatric diseases likely share genetic risk factors.…”

Exposure to a single immobilization or lipopolysaccharide challenge increases expression of genes implicated in the development of Alzheimer’s disease in the mice brain cortex

“…However, in our experimental model, there were no significant changes seen in the gene expression of markers studied indicating for the brain immune activity by neuronal CD200 and its microglial receptor CD200R (Yi et al 2012), or suppression of inflammatory cytokines release from microglia mediated by TREM2 (Mecca et al 2018) ( Figure 5). Restricted expression of the chemokine receptor CX3CR1 in microglia (Wolf et al 2013), as one of the stress-responsive gene involved in neuroinflammation accompanying neurodegenerative tau pathology, has been described in rats (Novak et al 2018). But we did not observe any changes in the expression of CX3CR1 in mice cortex indicating for a quiescent "sampling" or surveillance mode of microglia as it has previously been reviewed (Biber et al 2007).…”