Tauopathy in transgenic (SHR72) rats impairs function of central noradrenergic system and promotes neuroinflammation

Abstract

BackgroundBrain norepinephrine (NE) plays an important role in the modulation of stress response and neuroinflammation. Recent studies indicate that in Alzheimer’s disease (AD), the tau neuropathology begins in the locus coeruleus (LC) which is the main source of brain NE. Therefore, we investigated the changes in brain NE system and also the immune status under basal and stress conditions in transgenic rats over-expressing the human truncated tau protein.MethodsBrainstem catecholaminergic cell groups (LC, A1, and A2) and forebrain subcortical (nucleus basalis of Meynert), hippocampal (cornu ammonis, dentate gyrus), and neocortical areas (frontal and temporal association cortices) were analyzed for NE and interleukin 6 (IL-6) mRNA levels in unstressed rats and also in rats exposed to single or repeated immobilization. Moreover, gene expression of NE-biosynthetic enzyme, tyrosine hydroxylase (TH), and several pro- and anti-inflammatory mediators were determined in the LC.ResultsIt was found that tauopathy reduced basal NE levels in forebrain areas, while the gene expression of IL-6 was increased in all selected areas at the same time. The differences between wild-type and transgenic rats in brain NE and IL-6 mRNA levels were observed in stressed animals as well. Tauopathy increased also the gene expression of TH in the LC. In addition, the LC exhibited exaggerated expression of pro- and anti-inflammatory mediators (IL-6, TNFα, inducible nitric oxide synthases 2 (iNOS2), and interleukin 10 (IL-10)) in transgenic rats suggesting that tauopathy affects also the immune background in LC. Positive correlation between NE and IL-6 mRNA levels in cornu ammonis in stressed transgenic animals indicated the reduction of anti-inflammatory effect of NE.ConclusionsOur data thus showed that tauopathy alters the functions of LC further leading to the reduction of NE levels and exaggeration of neuroinflammation in forebrain. These findings support the assumption that tau-related dysfunction of LC activates the vicious circle perpetuating neurodegeneration leading to the development of AD.

Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease

“…dentate gyrus) in TgF344-AD animals, suggesting an interaction between intracellular tau and the extracellular microenvironment. Similar loss of forebrain NE was observed in SHR72 rats overexpressing a pathogenic truncated form of human tau [54]. Moreover, cultured LC neurons from P301S mice have normal cell viability but shorter neurites, and 10-month old P301S animals have a significant reduction of NE in the hippocampus compared to wild-type littermates, again implicating a direct effect of aberrant tau [41, 42].…”

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease

“…Forebrain neuroinflammation is a hallmark of many neurodegenerative diseases; however, few studies have investigated inflammation in the locus coeruleus (Heneka et al, 2015). In rats, human tau increases the expression of inflammatory cytokines in the locus coeruleus, and chronic administration of lipopolysaccharide increases microglial infiltration and degeneration (Bardou et al, 2014;Mravec et al, 2016). Pretangle tau, microglia and locus coeruleus degeneration are found in patients with more advanced Alzheimer's disease, after Braak stage III (Andres-Benito et al, 2017;Ehrenberg et al, 2017;Kelly et al, 2017).…”

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

“…During aging, decline of the LC-NE system is associated with reduced cognitive abilities relating to episodic memory and reduced cognitive reserve ( Betts et al, 2019 ). Cumulative evidence suggests that aberrant tau accumulation in the LC and noradrenergic dysfunction are critical early events in the progression of AD ( Mravec et al, 2016 ; Rorabaugh et al, 2017 ; Matchett et al, 2021 ). Aβ aggregation can also cause axonal degeneration in LC neurons ( Sakakibara et al, 2021 ).…”