Editorial: Molecular and epigenetic mechanisms in neuroinflammation and neurodegeneration

Edi o ial: Molecula and epigene ic mechanisms in neu oinflamma ion and neu odegene a ion Isaac F ancos-Quijo na 1 * † , Elisa Ca asco 2 * † and En ique Gabandé-Rod íguez 3 * † 1 Depa men o Molecula Biology, Facul y o Sciences, Uni e sidad Au ónoma de Mad id (UAM), Mad id, Spain, 2 Depa men o Biology, Facul y o Sciences, Uni e sidad Au ónoma de Mad id, Mad id, Spain, 3 Tissue and O gan Homeos asis P og am, Cen o de Biología Molecula Se e o Ochoa (CBMSO), Consejo Supe io de In es igaciones Cien íficas (CSIC), Mad id, Spain KEYWORDS aging, neu odegene a ion, epigene ics, neu oinflamma ion, age-associa ed diseases Edi o ial on he Resea ch Topic Molecula and epigene ic mechanisms in neu oinflamma ion and neu odegene a ion In oduc ion The sus ained inc ease in li espan expec ancy achie ed du ing he las yea s has c i ically inc eased he in e es in unde s anding he molecula and cellula mechanisms igge ing age- ela ed diseases. Aging is a na u al biological p ocess ha leads o a p og essi e decline in physiological unc ions, making indi iduals mo e suscep ible o a ious age- ela ed diseases. In his Resea ch Topic, Lee e al. e iew and emphasize he con ibu ion o immunosenescence o he unc ional decline o he immune sys em du ing aging. Among o he ea u es, senescen cells ypically accumula ed in he issues du ing aging a e cha ac e ized by he p o-inflamma o y senescence associa ed sec e o y pheno ype (SASP), con ibu ing o d i e local and sys emic ch onic s e ile inflamma ion h ough he sec e ion o mul iple cy okines and chemokines. Among he senescen signa u es ha appea in he majo popula ions o immune cells, p e ious epo s unco e ed he dec eased ex en o ype I IFN esponses d i en by inna e immune cells is highligh ed as a isk ac o o i al in ec ions in aged indi iduals (Bas a d e al., 2020). In pa allel, ine ficien an ibody p oduc ion by B cells is coupled wi h age-associa ed al e a ions in he unc ion o ollicula helpe T cells (Almanan e al., 2020), oge he wi h de ec i e clea ance o senescen cells om he issues and excessi e and p omiscuous p oduc ion o cy o oxic molecules by cy o oxic T cells (Sua ez-Ál a ez e al., 2017;Pe ei a e al., 2020). Al oge he , hese age-associa ed al e a ions in di e en senescen immune cell popula ions con ibu e o immune dys unc ion du ing aging. The au ho s highligh ha apa om cell-au onomous esponses, he al e ed aged en i onmen can nega i ely a ec immune cell unc ion. The exposu e o i al and bac e ial agen s exemplified by SARS-CoV-2 can also ins iga e OPEN ACCESS EDITED AND REVIEWED BY Consuelo Bo as, Uni e si y o Valencia, Spain *CORRESPONDENCE Isaac F ancos-Quijo na, [email p o ec ed]s Elisa Ca asco, [email p o ec ed] En ique Gabandé-Rod íguez, [email p o ec ed] † These au ho s ha e con ibu ed equally o his wo k RECEIVED 02 Augus 2023 ACCEPTED 08 Augus 2023 PUBLISHED 14 Augus 2023 CITATION F ancos-Quijo na I, Ca asco E and Gabandé-Rod íguez E (2023), Edi o ial: Molecula and epigene ic mechanisms in neu oinflamma ion and neu odegene a ion. F on . Aging 4:1271714. doi: 10.3389/ agi.2023.1271714 COPYRIGHT © 2023 F ancos-Quijo na, Ca asco and Gabandé-Rod íguez. This is an open- access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. F on ie s in Aging on ie sin.o g01 TYPE Edi o ial PUBLISHED 14 Augus 2023 DOI 10.3389/ agi.2023.1271714 senescence and con ibu e o immune cell dys unc ion ha a ou s inc eased mul imo bidi y, wi h highe impac on he elde ly. Majo age-associa ed pa hologies include neu odegene a i e diso de s like Alzheime ’s disease (AD). One o he key challenges in diagnosing neu odegene a i e diseases is he di ficul y in dis inguishing be ween physiological aging and pa hological aging. Iden i ying bioma ke s ha flag his ansi ion would p o ide an ea lie de ec ion and he apeu ic op ions. In his ega d, ecen findings poin o a p ominen ole o neu oinflamma ion in igge ing neu odegene a i e diseases. While he ole o myeloid cells, and specially mic oglia, was well es ablished, how he adap i e immune sys em con ibu es o neu odegene a i e diseases is p og essi ely acqui ing mo e ele ance in his esea ch field. Indeed, ecen findings ha e e idenced ha cy o oxic T cells accumula e in he b ain o mouse models and pa ien s wi h pa hologies like AD, Amyo ophic la e al scle osis o Pa kinson’s disease (Ca asco e al., 2022). In his opic, Cox e al. e iewed he po en ial o glu ama e, a c ucial neu o ansmi e in he b ain, as a bioma ke o iden i ying his pa hological ansi ion in AD. Du ing heal hy aging, has been epo ed a dec ease in glu ama e gic synapses and neu ons mainly in he hippocampus, p e on al co ex and mo o senso y a eas which in combina ion wi h g ey ma e hinning helps o explain he subsequen cogni i e, mo o and senso y decline in heal hy aging (Sego ia e al., 2001;Gasio owska e al., 2021). Howe e , con a y o heal hy aging, esea ch on bo h human pa ien s and animal models (Minke iciene e al., 2008;Mu a e al., 2012;Hascup e al., 2016; Hascup e al., 2021) showed ha ea ly s ages o AD a e associa ed wi h hype ac i e glu ama e signaling in hippocampus, p eceding o coinciding wi h amyloid and/o au accumula ion, while la e s ages show educed glu ama e le els due o neu onal loss. The e o e, as Cox e al. highligh in hei e iew, he use o non-in asi e imaging me hods o moni o glu ama e le els, such as ce eb ospinal fluid analysis, PET imaging, MRS, and GluCEST migh open a enues o ea ly he apeu ic in e en ions aimed a mi iga ing cogni i e decline in AD pa ien s. Rega ding neu oinflamma ion, Zhuang e al. in es iga ed he in ol emen o immune cell- ela ed genes and bioma ke s in AD de elopmen and p og ession. They used bioin o ma ic me hods o find di e en ially exp essed genes (DEGs) be ween AD and con ol samples in h ee di e en da abases, and by CIBERSORT algo i hm hey co ela ed hose genes wi h di e en ially infil a ed immune cells (DIICs) (Zhuang e al.). They epo ed ha , in line wi h ecen li e a u e da a (Heneka e al., 2015;Chen and Hol zman, 2022), se e al immune cell ypes, including NK cells, mac ophages, dend i ic cells, and T cells, showed significan di e ences in infil a ion be ween AD and con ol samples. Nex , a e u he na owed down he ocus o immune cell- ela ed DEGs ha we e highly co ela ed wi h specific immune cell ypes by WGNA analysis, hen machine lea ning me hods we e employed o iden i y a se o en obus immune cell- ela ed genes (CMTM2, DDIT4, LDHB, NDUFA1, NDUFB2, NDUFS5, RPL17, RPL21, RPL26, and NDUFAF2) as po en ial bioma ke s o AD. Then, a e alida ing he exp ession ends o hese genes in pe iphe al blood samples om AD pa ien s and heal hy olun ee s by qPCR, au ho s cons uc ed a diagnos ic nomog am by di e en bioma ke combina ion, as a ool o es ima e he p obabili y o disease p esence showing p omising esul s in diagnos ic accu acy. Finally, hey p edic ed some chemicals, including es e a ol, ha could a ge he iden ified genes and po en ially se e as he apeu ic agen s in AD ea men using he Compa a i e Toxicogenomics Da abase (CTD) and bioin o ma ic app oaches. In conclusion, Zhuang e al.’s epo iden ified se e al immune-cell- ela ed genes as eliable bioma ke s in AD pa hogenesis, and hei diagnos ic monog am o e s an impo an ool o ea ly AD diagnosis despi e he need o addi ional esea ch and alida ion s udies. Recen esea ch is ying o es ablish whe he neu oinflamma ion is a p ocess occu ing exclusi ely h ough he engagemen o cell-in insic molecula pa hways o whe he ex insic o sys emic ac o s con ibu e o he ac i a ion o immune cells. The ele ance o his ex ends beyond basic scien ific knowledge as li es yle habi s can influence inflamma ion and so, can unco e po en ial a ge s o pha macological in e en ion in hese diseases. In his ega d, F aus o e al. epo in his opic ha a mouse model o AD o ced o inges alcohol, de elops abno mal in es inal pe meabili y and al e ed composi ion o he gu mic obiome (in es inal dysbiosis). This co ela es wi h inc eased sys emic le els o he p o-inflamma o y cy okine in e leukin-6 (IL-6) and inc eased le els o p o-inflamma o y ma ke s in hei b ains. Mo eo e , hey ound a significan co ela ion o ce ain bac e ial species such as Lachnospi aceae NK4A136 and Clos idium sensu s ic o 1 wi h he al e ed beha iou and he appea ance o disease ma ke s in he b ain o hese mice (F aus o e al.). These findings align wi h ecen epo s ha ound ha al e ed gu mic obio a composi ion may be an indica o o p eclinical AD in pa ien s (Fe ei o e al., 2023). Finally, in his opic E ic Mayo e iews he po en ial neu o ophic e ec s o calo ie es ic ion, exe cise p ac ice o in e mi en as ing; sugges ing ha implemen a ion o any o e en a combina ion o hese ac o s could con ibu e o imp o e he ou come o pa ien s su e ing neu odegene a i e diseases. In e es ingly, impo an molecula pa hways such as mTOR, NF- ĸB, PGC-1α, MAPK o GSK-3βa e a ge s o hese in e en ions (Mayo ). This highligh s ha esea ch on his field may b ing he iden ifica ion o al e ed, po en ially d uggable, molecula pa hways in hese diseases and no only he cha ac e iza ion o he e ec s o hese in e en ions ha a e un o una ely no always easy o implemen in hese kind o pa ien s. Conclusion This opic includes o iginal pape s and e iew a icles summa izing he con ibu ion o di e en mechanisms anging om exogenously inges ed damaging agen s, p o-inflamma o y molecules o exace ba ed neu o ansmi e elease o neu odegene a ion and age-associa ed cogni i e decline. Mo eo e , he opic p o ides wi h po en ial he apeu ic op ions ha could amelio a e he impai ed neu onal pe o mance, which is cha ac e is ic o hese condi ions. On op o ha , he eade s will also find esea ch on new ma ke s ha will e en ually help diagnosing hese condi ions a ea lie s ages. Fu u e esea ch mus deepen in o why common mechanisms a e al e ed du ing he p og ession o diseases wi h di e en ae iology, wha could defini ely make an impac in pa ien s’weelbeing. F on ie s in Aging on ie sin.o g02 F ancos-Quijo na e al. 10.3389/ agi.2023.1271714 Au ho con ibu ions IF-Q: Concep ualiza ion, Funding acquisi ion, In es iga ion, P ojec adminis a ion, Supe ision, Valida ion, Visualiza ion, W i ing–o iginal d a , W i ing– e iew and edi ing. EC: Concep ualiza ion, Da a cu a ion, Fo mal Analysis, Funding acquisi ion, In es iga ion, Me hodology, P ojec adminis a ion, Resou ces, So wa e, Supe ision, Valida ion, Visualiza ion, W i ing–o iginal d a , W i ing– e iew and edi ing. EG-R: Concep ualiza ion, Da a cu a ion, Fo mal Analysis, Funding acquisi ion, In es iga ion, Me hodology, P ojec adminis a ion, Resou ces, So wa e, Supe ision, Valida ion, Visualiza ion, W i ing–o iginal d a , W i ing– e iew and edi ing. Funding This s udy was suppo ed by he Y2020/ BIO6350 Nu iSION-CM g an unded by Comunidad de Mad id. EG-R is suppo ed by ERC-2021-CoG-101044248-Le T Be. IF-Q is suppo ed by a Juan de la Cie a (JC2020-044392) con ac om he spanish minis y o science. Conflic o in e es The au ho s decla e ha he esea ch was conduc ed in he absence o any comme cial o financial ela ionships ha could be cons ued as a po en ial conflic o in e es . Publishe ’s no e All claims exp essed in his a icle a e solely hose o he au ho s and do no necessa ily ep esen hose o hei a filia ed o ganiza ions, o hose o he publishe , he edi o s and he e iewe s. Any p oduc ha may be e alua ed in his a icle, o claim ha may be made by i s manu ac u e , is no gua an eed o endo sed by he publishe . Re e ences Almanan, M., Rayno , J., Ogunsuli e, I., Malyshkina, A., Mukhe jee, S., Hummel, S. A., e al. (2020). IL-10-p oducing T h cells accumula e wi h age and link inflamma ion wi h age- ela ed immune supp ession. Sci. Ad . 6 (31), eabb0806. doi:10.1126/sciad . abb0806 Bas a d, P., Rosen, L. B., Zhang, Q., Michailidis, E., Ho mann, H. H., Zhang, Y., e al. (2020). Au oan ibodies agains ype I IFNs in pa ien s wi h li e- h ea ening COVID-19. Science 370 (6515), eabd4585. doi:10.1126/science.abd4585 Ca asco, E., Gómez de Las He as, M. M., Gabandé-Rod íguez, E., Desdín-Micó, G., A anda, J. F., Mi elb unn, M., e al. (2022). The ole o T cells in age- ela ed diseases. Na . Re . Immunol. 22 (2), 97–111. doi:10.1038/s41577-021-00557-4 Chen, X., and Hol zman, D. M. (2022). Eme ging oles o inna e and adap i e immuni y in Alzheime ’s disease. Immuni y 55 (12), 2236–2254. doi:10.1016/j.immuni. 2022.10.016 Fe ei o, A. L., Choi, J., Ryou, J., Newcome , E. P., Thompson, R., Bollinge , R. M., e al. (2023). Gu mic obiome composi ion may be an indica o o p eclinical Alzheime ’s disease. Sci. T ansl. Med. 15 (700), eabo2984. doi:10.1126/sci anslmed. abo2984 Gasio owska, A., Wyd ych, M., D apich, P., Zad ozny, M., S eczkowska, M., Niewiadomski, W., e al. (2021). The biology and pa hobiology o glu ama e gic, choline gic, and dopamine gic signaling in he aging b ain. F on . aging Neu osci. 13, 654931. doi:10.3389/ nagi.2021.654931 Hascup, K. N., Findley, C. A., B i z, J., Espe an -Hilai e, N., B ode ick, S. O., Delfino, K., e al. (2021). Riluzole a enua es glu ama e gic one and cogni i e decline in AβPP/ PS1 mice. J. Neu ochem. 156 (4), 513–523. doi:10.1111/jnc.15224 Hascup,K.N.,Hascup,E.R.,Hascup,K.N.,B i z,J.,Findley,C.A.,Tischkau,S.,e al.(2016). Soluble amyloid-β42 s imula es glu ama e elease h ough ac i a ion o he α7 nico inic ace ylcholine ecep o . J. Alzheime s Dis. 53 (1), 337–347. doi:10.3233/JAD-160041 Heneka, M. T., Ca son, M. J., El Khou y, J., Land e h, G. E., B osse on, F., Feins ein, D. L., e al. (2015). Neu oinflamma ion in Alzheime ’s disease. Lance Neu ology 14 (4), 388–405. doi:10.1016/S1474-4422(15)70016-5 Minke iciene, R., Ihalainen, J., Malm, T., Ma ilainen, O., Keksa-Golds eine, V., Golds eins, G., e al. (2008). Age- ela ed dec ease in s imula ed glu ama e elease and esicula glu ama e anspo e s in APP/PS1 ansgenic and wild- ype mice. J. Neu ochem. 105 (3), 584–594. doi:10.1111/j.1471-4159.2007.05147.x Mu a, E., Zappe ini, S., P eda, S., Biundo, F., Lanni, C., G illi, M., e al. (2012). Dual e ec o be a-amyloid on α7 and α4β2 nico inic ecep o s con olling he elease o glu ama e, aspa a e and GABA in a hippocampus. PLoS One 7 (1), e29661. doi:10. 1371/jou nal.pone.0029661 Pe ei a, B. I., De Maeye , R. P. H., Co e, L. P., Neha -Belaid, D., Lanna, A., Wa d, S., e al. (2020). Ses ins induce na u al kille unc ion in senescen -like CD8(+) T cells. Na . Immunol. 21 (6), 684–694. doi:10.1038/s41590-020-0643-3 Sego ia, G., Po as, A., Del A co, A., Mo a, F., Gasio owska, A., Wyd ych, M., e al. (2001). Glu ama e gic neu o ansmission in aging: a c i ical pe spec i e. Mech. Ageing De . 122 (1), 1–29. doi:10.1016/s0047-6374(00)00225-6 Sua ez-Ál a ez, B., Rod íguez, R. M., Schlangen, K., Rane os, A. B., Má quez- Kisinousky, L., Fe nández, A. F., e al. (2017). Pheno ypic cha ac e is ics o aged CD4(+) CD28(null) T lymphocy es a e de e mined by changes in he whole- genome DNA me hyla ion pa e n. Aging Cell. 16 (2), 293–303. doi:10.1111/acel.12552 F on ie s in Aging on ie sin.o g03 F ancos-Quijo na e al. 10.3389/ agi.2023.1271714