Abstract
One of the characteristics of the cerebral aging process is the presence of chronic inflammation through glial cells, which is particularly significant in neurodegeneration. On the other hand, it has been demonstrated that the aryl hydrocarbon receptor (AHR) participates in the inflammatory response. Currently, evidence in animal models shows that the hallmarks of aging are associated with changes in the AHR levels. However, there is no information concerning the behavior and participation of AHR in the human aging brain or in Alzheimer’s disease (AD). We evaluated the expression of AHR in human hippocampal post-mortem tissue and its association with reactive astrocytes by immunohistochemistry. Besides this, we analyzed through ELISA the AHR levels in blood serum from young and elder participants, and from AD patients. The levels of AHR and glial fibrillar acid protein were higher in elder than in young post-mortem brain samples. AHR was localized mainly in the cytosol of astrocytes and displayed a pattern that resembles extracellular vesicles; this latter feature was more conspicuous in AD subjects. We found higher serum levels of AHR in AD patients than in the other participants. These results suggest that AHR participates in the aging process, and probably in the development of neurodegenerative diseases like AD.
Highlights
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely known for its role in mediating the detoxification of xenobiotics
When AHR interacts with its ligands, it undergoes conformational changes that expose its nuclear localization sequence, promoting AHR translocation to the nucleus, where it heterodimerizes with the AHR nuclear translocator (ARNT)
The complex formed by the AHR–ligand–ARNT binds to specific DNA regions called xenobiotics response elements or dioxin response elements located in the promoter regions of their target genes, to regulate their expression [1]
Summary
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely known for its role in mediating the detoxification of xenobiotics. Taking into account the central role that AHR has in inflammation, and the scarce information about human AHR in conditions characterized by chronic low-grade inflammation, like aging and Alzheimer’s disease, in the present study, we evaluated the changes in the expression of AHR and GFAP in human hippocampal post-mortem tissue from young and elder subjects. Considering the effect that we observed with microangiopathy, we decided to carry out subsequent analyses only with AD patients without this comorbidity In this way, the expression of AHR was dramatically increased in AD patients compared with the elderly (t = 3.671, df = 33, p = 0.0008, Figure 6A), and the AHR levels in AD patients were not associated with disease severity (F(2,18) = 0.4772, p = 0.6291; Figure 6B). The data show an apparent increase in the expreFsFisgiigouunrereo5f.5.AAAHHHRRRiniinnccrfereeamasesaeilniensAAcDoDbmbloplooaodrdesdeserurwumimt.h.WWmeeadldeeetseterimrnmitnihneeeddeAlAdHHeRrRliynin(speseru=rum0m.1frf3or1om6m)thtaheneydyooAuunDngg,(,hpheea=alt0lht.hy0y768) patieneteldsld.eer,Fra,uanrndtdhAeADrDmpopaarteitei,enntmsts.a.WWleeefAfoouDunnddphhaitiggiehhneertrsAAHHdiRRspccoloannycceeednnttrraathttiieoonnhiinnigAAhDeDsptpaatctiioeennntctsse(n(nnt=r=a2t29io9) )tnhthaonafniniAnyHoyuoRnugnwg(nhen comp(an=re=1d41)4w)ainatdnhdtehledledeerellrydlye(nr(nm==a11l6e6))gppraaorrtutiicpciippwaanintthtsso((uAAt));;AmmDiicc(rrtooa=ann3gg.i3ioo8pp3aa,tthdhyfy=((MM14AA,GGp,, =nn 0==.0110004))5iis,sFaaicgocuomrmeoor4brCbidi)di.tiSytyitmhthailatatrly, femaldedeAecrcDereaapsesaestsitehtnheetAsAHhHaRdRlealvehveielglinhineArADsDeprpautamiteinelntestvs(eB(lB)o.).fVVAalauHlueRsesathraeraemnmeealednaen±r±fSeSEmEMMa.l.SeStsat(attitsi=tsitc3isc.0sw1w5eer,erdepfpe=ref1rof7or,mrpme=edd0b.by0y078, Figurueun6npCpa)ai.rierdedt-tt-etsets.t.WWeeddididnnoot tddeteetcetctsisgignnifiifciacnant dt diffifefreernecnecseisninvavraiarinacnecseus suisnigngananF-Fte-tsets. t
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