Beneficial effects of curtailing immune susceptibility in an Alzheimer’s disease model

Abstract

Background Currently, there are no effective therapeutic options for Alzheimer’s disease, the most common, multifactorial form of dementia, characterized by anomalous amyloid accumulation in the brain. Growing evidence points to neuroinflammation as a major promoter of AD. We have previously shown that the proinflammatory cytokine TNFSF10 fuels AD neuroinflammation, and that its immunoneutralization results in improved cognition in the 3xTg-AD mouse. Methods Here, we hypothesize that inflammatory hallmarks of AD might parallel with central and peripheral immune response dysfunction. To verify such hypothesis, we used a triple transgenic mouse model of AD. 3xTg-AD mice were treated for 12 months with an anti-TNFSF10 antibody, and thereafter immune/inflammatory markers including COX2, iNOS, IL-1β and TNF-α, CD3, GITR, and FoxP3 (markers of regulatory T cells) were measured in the spleen as well as in the hippocampus. Results Spleens displayed accumulation of amyloid-β 1–42 (Aβ 1-42 ), as well as high expression of Treg cell markers FoxP3 and GITR, in parallel with the increased levels of inflammatory markers COX2, iNOS, IL-1β and TNF-α, and blunted IL-10 expression. Moreover, CD3 expression was increased in the hippocampus, consistently with FoxP3 and GITR. After chronic treatment of 3xTg-AD mice with an anti-TNFSF10 antibody, splenic FoxP3, GITR, and the above-mentioned inflammatory markers expression was restored to basal levels, while expression of IL-10 was increased. A similar picture was observed in the hippocampus. Such improvement of peripheral and CNS inflammatory/immune response was associated with decreased microglial activity in terms of TNFα production, as well as decreased expression of both amyloid and phosphorylated tau protein in the hippocampus of treated 3xTg-AD mice. Interestingly, we also reported an increased expression of both CD3 and FoxP3, in sections from human AD brain. Conclusions We suggest that neuroinflammation in the brain of 3xTg-AD mice triggered by TNFSF10 might result in a more general overshooting of the immune response. Treatment with an anti-TNFSF10 antibody blunted inflammatory processes both in the spleen and hippocampus. These data confirm the detrimental role of TNFSF10 in neurodegeneration, and corroborate the hypothesis of the anti-TNFSF10 strategy as a potential treatment to improve outcomes in AD. Electronic supplementary material The online version of this article (10.1186/s12974-019-1554-9) contains supplementary material, which is available to authorized users.

Differential Effects of Chronic Immunosuppression on Behavioral, Epigenetic and Alzheimer’s Disease-Associated Markers in 3xTg-AD Mice

“…This nding is particularly interesting in light of reports that Aβ itself may have innate immune functions like antimicrobial activity [59,72] and that disruption of immune pathways attenuates Aβ burden [89]. Restoration of increased splenic Foxp3 + Tregs to basal levels has previously been shown to coincide with a reduction in the expression of Aβ in the hippocampus of 3xTg-AD males [27]. Using CY, we see similar lessening of Aβ burden in the cortex of 3xTg-AD males and females.…”

“…Since human Aβ has recently been reported in the spleens of 15-month-old 3xTg-AD males [27] and blood of 5-9-month-old 3xTg-AD females [23], we may speculate that peripheral Aβ might further exacerbate peripheral immune responses.…”

“…Coinciding with these behavioral changes is the spontaneous development of a progressive systemic autoimmune response, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit and increased number of double-negative T splenocytes [65]. Importantly, this immune activation in 3xTg-AD males manifests as early as 1.5 month of age, well before the earliest documented signs of neuropathology [65], and persists even at older ages [27]. When compared to wild-type males, AD males also show increased expression of macroH2A1, (mH2A1) [53], which is a variant of the canonical histone H2A, important in neuroplasticity and often upregulated during neurodegenerative processes [29,46].…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…There are observations that the number of Treg cells becomes increased in the blood of the patients with mild cognitive impairment (MCI) and AD [180]. Moreover, Di Benedetto et al [181] demonstrated that the number of FoxP3-positive cells, a key marker of Tregs, was significantly elevated in the hippocampus of post-mortem AD samples as compared with that of age-matched controls. A similar phenomenon was observed in the brains of transgenic AD mice.…”

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

“…Environmental factors, such as trauma and stressful life events, profoundly alter neural structure and functional plasticity of the brain, drives changes in physiology and behavior, and contributes to a variety of mental disorders [5]. Although the mechanism underlying PICS remains largely unexplored, the pathobiology of psychiatric conditions is closely linked to inflammatory processes [22][23][24]. Similarly, we showed signs of hippocampal inflammation in the form of glia overactivation and hypersecretion of inflammatory cytokines.…”