Abstract
BackgroundThe presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer’s disease and related tauopathies. However, the role of inflammation and anti-inflammatory interventions in tauopathies is unclear. Our goal was to determine if removing anti-inflammatory interleukin-10 (IL-10) during an acute inflammatory challenge has any effect on neuronal tau pathology.MethodsWe induce systemic inflammation in Il10-deficient (Il10−/−) versus Il10+/+ (Non-Tg) control mice using a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) to examine microglial activation and abnormal hyperphosphorylation of endogenous mouse tau protein. Tau phosphorylation was quantified by Western blotting and immunohistochemistry. Microglial morphology was quantified by skeleton analysis. Cytokine expression was determined by multiplex electro chemiluminescent immunoassay (MECI) from Meso Scale Discovery (MSD).ResultsOur findings show that genetic deletion of Il10 promotes enhanced neuroinflammation and tau phosphorylation. First, LPS-induced tau hyperphosphorylation was significantly increased in Il10−/− mice compared to controls. Second, LPS-treated Il10−/− mice showed signs of neurodegeneration. Third, LPS-treated Il10−/− mice showed robust IL-6 upregulation and direct treatment of primary neurons with IL-6 resulted in tau hyperphosphorylation on Ser396/Ser404 site.ConclusionsThese data support that loss of IL-10 activates microglia, enhances IL-6, and leads to hyperphosphorylation of tau on AD-relevant epitopes in response to acute systemic inflammation.
Highlights
The presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer’s disease and related tauopathies
Relevant phosphorylated tau epitopes at Ser202/Thr205, Thr231, and Ser396/Ser404 detected by AT8, AT180, and PHF-1 antibodies, respectively, can serve as markers for tau pathology [35,36,37]
No significant differences were found in the basal levels of phosphorylated tau or total tau between Il10−/− and Non-Tg mice treated with Veh
Summary
The presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer’s disease and related tauopathies. IL-10 plays a role in downregulating inflammatory responses in a variety of cell types [17] including microglia in the brain [18]. A compelling study by Chackrabarty et al has suggested that adenoassociated viral vector-mediated overexpression of IL-10 in amyloid-precursor protein (APP) mouse model of AD exacerbated amyloid pathology and cognitive impairment due to stunted phagocytic ability of microglia [23, 24]. It is still unclear whether or not IL-10 plays any regulatory role in tau pathology. We hypothesized that IL-10 plays a role in regulating the proinflammatorypathway that contributes to tau phosphorylation within the brain
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