Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

Abstract

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1β . In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1β impairment. In hippocampal neuronal cultures, IL-1β increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1β. To evaluate whether synapses develop a similar heightened sensitivity to IL-1β with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1β impairs LTP directly at the synapse and that sensitivity to IL-1β is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1β was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1β levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1β. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1β-mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1β that occurs with age.AcP | AcPb | neuroinflammation | receptor sensitivity | LTP

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

“…The effect we found on episodic memory is in line with a broad scientific literature that indicates that p38 α in involved in oligomeric amyloid‐beta and inflammation‐induced synaptic dysfunction and to stress‐ and age‐related synaptic dysfunction in the hippocampus 4, 5, 10, 11, 12, 13, 14, 31. In our clinical study, the ES that we saw for immediate and delay recall compares favorably to ES of ≤0.2 for WMS immediate or delayed recall at week 12 in the placebo‐treated subjects in two trials of Souvenaid in a similar patient population (mild AD, baseline MMSE = 24) 32, 33.…”

“…Traditionally p38 α kinase is considered to be an inflammation‐related target as microglial p38 α promotes production of proinflammatory cytokines6 and modulates microglial activation state,7, 8 and in the healthy state p38 α expression within neurons is low 9. However, more recent findings indicate that neuronal p38 α is increased in disease and under stress, and neuronal p38 α expression has been implicated in amyloid‐beta and/or inflammation‐induced synaptic dysfunction,10, 11, 12, 13, 14 specifically impaired synaptic plasticity. Consistent with the biology of neuronal p38 α , selective small molecule inhibitors of p38 α rapidly (i.e., within 2–3 weeks) reverse spatial learning defects in the APP/PS1 mouse model,15 aged rats16 and in tauopathy (hTau) mouse model 17…”

H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus

“…We identified the effect of ETP69 on hippocampal spine formation using Golgi staining and flow synaptometry, a new method that can be used to profile synapses using isolated synaptosomes (Prieto et al, 2015). Overall, our data reveal that ETP69 has procognitive benefits for the aging brain and that this effect supports a role of H3K9me3 in memory function.…”

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…We initially selected an age with no sign of pathology (3 months; Figure 1a) and another when amyloid or tau pathology is just emerging (7–8 months; Figure 1b). Synaptic plasticity in hippocampal synaptosomes was assessed by fluorescence analysis of single‐synapse long‐term potentiation (FASS‐LTP) (Prieto et al., 2015). This flow cytometry‐based method induces chemical LTP in freshly isolated synaptosomes by chemical stimulation and tracks the insertion of glutamate AMPARs (GluA1) in the postsynaptic surface and Neurexin1β (Nrx1β) in the presynaptic surface, to ensure that intact synaptosomes contain both presynaptic and postsynaptic elements (Prieto et al., 2015).…”

“…A detailed description of the methods including tissue processing, culture of cells, immunotherapy treatment, and electrophysiological (fluorescence analysis of single‐synapse long‐term potentiation and microtransplantation of synaptic membranes), histological (immunohistochemistry, Golgi stain, electron microscopic preparation, cresyl violet stain), and biochemical (immunoblot, dot blot, ELISA, gene expression analysis) techniques used in the current manuscript is added as supplemental data (Baglietto‐Vargas et al., 2015; Caccamo et al., 2010; Limon et al., 2012; Oddo et al., 2003; Prieto et al., 2015; Sanchez‐Varo et al., 2012). …”