Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice

Abstract

Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post-septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element-binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer), and GluA1 phosphorylated at serine residue 845 (GluA1pSer). Expression of tumor necrosis factor α (TNF-α) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer) and of GSK3 at serine 9 (GSK3βpSer) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3β inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors.

Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases

“…() and Talbot and Wang (). Similar recent studies into the cognitive impairment in a post‐sepsis mouse model (Neves et al ., ) showed the same detailed IR pathophysiology, including changes surrounding IRS‐1 and Akt, as well as a positive response to a glucagon‐like protein‐1 mimetic that reverses IR, as reported in AD in this study. In particular, infliximab completely blocks the Aβ‐induced inhibition of IRS‐1, the insulin receptor component discussed below in a tau context (Bomfim et al ., ).…”

Consequences of gestational diabetes to the brain and behavior of the offspring

“…Although preliminary, these early studies point out to GD as an important factor influencing offspring brain health. Moreover, studies from our group and others have recently described how inflammation and disrupted insulin signaling in memory-related brain regions occur in conditions that affect cognition (Bomfim et al 2012, Lourenço et al 2013, Neves et al 2016. Therefore, we also focus on the evidence suggesting that downregulation of insulin receptors and its intracellular cascade are seen in the brains of GD offspring and could contribute to affect their behavior.…”

“…These patients often present late cognitive impairment and some of them never fully recover (Iwashyna et al 2010, Pandharipande et al 2013, Semmler et al 2012. Using an experimental model of sepsis, we were able to mimic the late cognitive impairment seen in patients and found that increased hippocampal expression of TNF-α and impaired insulin signaling in this brain region also accompany sepsis-associated late cognitive decline (Neves et al 2016). Whether impaired brain insulin signaling is a common denominator of other conditions affecting memory remains to be established.…”

Modulation of MicroRNAs as a Potential Molecular Mechanism Involved in the Beneficial Actions of Physical Exercise in Alzheimer Disease

“…Increased expression of miR-200b or -c diminishes secretion of the Aβ oligomers and, consequently, reduces IRS-1 phosphorylation in serine residues, which is associated with cognitive impairment and memory loss in AD [ 142 , 143 , 144 ]. Exacerbated IRS-1 phosphorylation on serine residues may also induce dephosphorylation of protein kinase B (AKT) by inhibiting pro-survival signaling pathways and activation of glycogen synthase kinase-3β (GSK-3β), a cellular pathway that leads to neuronal apoptosis [ 145 ]. GSK-3β, in turn, inhibits the induction of the autophagosome to the lysosome and stimulates the insertion of the autophagosome to the multivesicular body (MVB).…”