Blocking IL-1 Signaling Rescues Cognition, Attenuates Tau Pathology, and Restores Neuronal β-Catenin Pathway Function in an Alzheimer’s Disease Model

Abstract

Inflammation is a key pathological hallmark of Alzheimer's disease (AD), though its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, interleukin-1β (IL-1β) in particular has been implicated in playing a pathogenic role. Here we sought to investigate whether inhibition of IL-1β signaling provides disease-modifying benefits in an AD mouse model, and if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1 receptor (IL-1R) blocking antibody significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β (Aβ). Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3β and p38-MAPK, and also reduces phospho-tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/β-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3β activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

“…We previously demonstrated that altered inflammation such as gliosis in the brain exacerbated tau pathology in 3xTg-AD mice (Kitazawa et al, 2005(Kitazawa et al, , 2011. Accordingly we investigated pathological changes in tau after upregulation of GLT-1.…”

“…As described previously (Kitazawa et al, 2011), the apparatus used for the MWM task was a circular aluminum tank (1.2-m diameter) painted white and filled with water maintained at 22e24 C. The maze was located in a room containing several simple visual extramaze cues. Mice were trained to swim and find a 14-cm diameter circular clear Plexiglas platform submerged 1.5 cm beneath the surface of the water and invisible to the mice while swimming.…”

“…Soluble and insoluble Ab 1-40 and Ab 1-42 levels were measured by enzyme-linked immunosorbent assay (ELISA) as previously described (Kitazawa et al, 2011). Briefly, 96-well plates (Immulon 2HB, Fisher Scientific, Waltham, MA, USA) were coated with 25 mg/mL of the mouse anti-Ab monoclonal antibody (clone 20.1) in carbonate coating buffer pH 9.6 (Sigma-Aldrich, St. Louis, MO, USA) and incubated overnight at 4 C. The wells were washed and blocked with 3% bovine serum albumin (BSA) overnight at 4 C with shaking.…”

Interleukin 1 Receptor and Alzheimer’s Disease-Related Neuroinflammation

“…The inhibition of IL-1 signaling signiicantly suppressed the activation of cdk5/p25, GSK-3β, and p38-MAPK, all major kinases that phosphorylate tau in neurons. Another study demonstrated a direct efect of IL-1β secreted by microglia on neurons and subsequent activation of p38-MAPK and accumulation of tau phosphorylation [69]. NSAIDs could be repurposed as NLRP3 inlammasome inhibitors that provide neuroprotective impact against AD [70].…”

“…IL-1β has been reported to increase the expression of APP in neuronal culture [69]. The amyloid precursor protein (APP), via stimulation of amyloidogenic processing, undergoes sequential proteolytic cleavage by β-secretase and γ-secretase to generate Aβ.…”