Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice

Abstract

CitationInterleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice. 2017, 140 Research, 2017, Vol. 45, No. 5 Published online 28 November 201628 November doi: 10.1093 ABSTRACTCentrosomal 190 kDa protein (CP190) is a promoter binding factor, mediates long-range interactions in the context of enhancer-promoter contacts and in chromosomal domain formation. All Drosophila insulator proteins bind CP190 suggesting a crucial role in insulator function. CP190 has major effects on chromatin, such as depletion of nucleosomes, high nucleosomal turnover and prevention of heterochromatin expansion. Here, we searched for enzymes, which might be involved in CP190 mediated chromatin changes. Eighty percent of the genomic binding sites of the histone acetyltransferase Gcn5 are colocalizing with CP190 binding. Depletion of CP190 reduces Gcn5 binding to chromatin. Binding dependency was further supported by Gcn5 mediated co-precipitation of CP190. Gcn5 is known to activate transcription by histone acetylation. We used the dCas9 system to target CP190 or Gcn5 to a Polycomb repressed and H3K27me3 marked gene locus. Both, CP190 as well as Gcn5, activate this locus, thus supporting the model that CP190 recruits Gcn5 and thereby activates chromatin.

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

“…It is likely that additional genes play a role, either independently or via an interaction with Trpc3, in determining severity of AD neuropathology. This idea is supported by the fact that positional candidates Fgf2 and Il2 have independently been associated with amyloid levels in model systems (Alves et al, 2017;Katsouri et al, 2015). In addition, the QTL identified in our AD-BXD panel does not overlap with those broad regions associated with pathology previously (Ryman et al, 2008;Sebastiani et al, 2006).…”

“…Three of these six genes, fibroblast growth factor 2 (Fgf2) (Donnini et al, 2006;Katsouri et al, 2015), cyclin A2 (Ccna2) (Chandrasekaran and Bonchev, 2016), and interleukin 2 (Il2) (Alves et al, 2017) have previously been associated with Aβ levels, suggesting variants in one or multiple genes in this region may influence amyloid load. Of the remaining 3 genes that had not been previously implicated as involved in amyloid accumulation, Trpc3 emerged as the gene with the most biological evidence for a potential functional role in AD.…”

A Link Between Alzheimer's and Type II Diabetes Mellitus? Ca+2‐Mediated Signal Control and Protein Localization

“…[30, 32] In neurons, IL-2 was shown to restore T-cell function and alleviate AD symptoms including the loss of synaptic plasticity and memory. [42] Thus, when Src and/or p52shc are away from the membrane, it appears to offer protective effects against disease-associated molecular events.…”

The role of regulatory T cells in nervous system pathologies

“…Systemic transfer of both standard CD4 + CD25 + cells, or CD4 + CD25 + cells following education with human umbilical cord mesenchymal stem cells, which increases their suppressive capacity, reduces Aβ plaque deposition and improves cognitive function in 3xTg and AβPPswe/PS1dE9 double‐transgenic mice, respectively (Baek et al, ; Yang, Yang, Xie, Wei, & Bi, ). Further, peripheral IL‐2 therapy, which stimulates Treg cell proliferation, has been shown to activate and expand Treg cell populations systemically and in the brain, induce astrocyte recruitment and activation around amyloid plaques in the hippocampus, increase plaque‐associated microglia, improve synaptic plasticity, reduce spine density, and restore cognitive function in animal models of Alzheimer's disease (Alves et al, ; Dansokho et al, ).…”