Pe spec i e o Molecula Neu odegene a ion
Nex -gene a ion hiPSC-based models o deciphe he con ibu ion o human
as ocy es o Alzheime ’s disease and po en ial a ge ing he apeu ics
Julia TCW1 and Amaia M A anz2,3
1 Depa men o Pha macology & Expe imen al The apeu ics, Bos on Uni e si y
Chobanian & A edisian School o Medicine, Bos on, USA.
2 Achuca o Basque Cen e o Neu oscience, Leioa, Spain
3 Ike basque Basque Founda ion o Science, Bilbao, Spain
Co espondence:
Julia TCW: julia[email p o ec ed]
Amaia M A anz: [email p o ec ed]
As ocy es cons i u e a la ge pa o he b ain cell mass and play essen ial unc ions in
he cen al ne ous sys em (CNS). They main ain b ain homeos asis, p o ide ophic
and me abolic suppo o neu ons, egula e synapse o ma ion, neu o ansmission and
calcium homeos asis, and con ol immune esponse and blood low. In Alzheime ’s
disease (AD), as ocy es unde go p o ound molecula , mo phological and unc ional
al e a ions ha a ise a ea ly s ages and exace ba e as disease e ol es, indica ing ha
as ocy es ansi ion om homeos a ic o dys unc ional disease-associa ed s a es and
poin ing o hese cells as c i ical con ibu o s o AD p og ession. Genome-wide
associa ion s udies (GWAS) suppo his idea as many pu a i e genes inc easing he
isk o de eloping la e-onse AD (LOAD) a e p ima ily exp essed in glial cells, among
which he majo AD isk genes APOE, CLU and FERMT2 a e p edominan ly exp essed
in as ocy es. While ou cu en knowledge o as ocy e con ibu ion o AD is mainly
coming om s udies in mouse models, c i ical species-speci ic di e ences highligh he
impo ance o s udying as ocy e (dys) unc ion in human-based sys ems. The abili y o
gene a e human induced plu ipo en s em cells (hiPSCs) om pa ien s and
di e en ia e hem in o as ocy es is p o iding exci ing oppo uni ies o explo e hei
unc ions in AD. We summa ize below ecen s udies in 2D and 3D cul u es, co-cul u e
sys ems and o ganoids gi ing essen ial clues on he impac o human as ocy es on
AD, and p opose po en ial as ocy e- a ge ing he apeu ics.
Ea lie s udies in 2D models e ealed ha heal hy hiPSC-de i ed as ocy es play
impo an oles in APP p ocessing, sec e e β-amyloid (Aβ) (1), and he e o e ha e he
po en ial o con ibu e o Aβ accumula ion in AD b ains. As ocy es de i ed om AD
pa ien s ca ying he PSEN1ΔE9 mu a ion display AD hallma ks including inc eased
Aβ and eac i e oxygen species (ROS) p oduc ion, al e ed in lamma o y esponses
and dys egula ed calcium homeos asis compa ed o isogenic con ol as ocy es (2).
When co-cul u ed wi h PSEN1 mu an as ocy es in a 3D sys em, isogenic con ol
neu ons also display al e a ions in calcium signaling (2), which highligh s a majo
impac o human as ocy es on human neu on physiology and unc ionali y.
In e es ingly, ac i a ion o NF-E2- ela ed ac o 2 (NRF2), key egula o o an ioxidan
de ense pa hways, educes Aβ sec e ion and modula es cy okine elease and
oxida i e s ess in PSEN1 mu an as ocy es (3), sugges ing ha a ge ing NRF2 in AD
as ocy es could be a po en ial he apeu ic s a egy.
As ocy es a e he majo cell ype exp essing and p oducing he p o ein apolipop o ein
E (apoE) in he b ain, al hough mic oglia, pa icula ly in an ac i a ed s a e, also p oduce
apoE. ApoE acili a es he anspo o lipids and choles e ol o neu ons, mic oglia and
oligodend ocy es, and binds o Aβ plaques. The APOE gene has h ee polymo phic
alleles (ε2, ε3 and ε4), being APOE4 he one con e ing he g ea es isk o LOAD wi h
an ea lie age o disease onse in a gene dose-dependen manne . Recen s udies
ha e s a ed o elucida e how APOE a ec s human as ocy e unc ions in he con ex
o AD. hiPSC-de i ed as ocy es ca ying he APOE4 a ian p oduce and sec e e less
apoE p o ein compa ed o APOE3 as ocy es, a e less e icien a clea ing he
ex acellula Aβ, and show impai ed lipid/choles e ol me abolism (4,5). As ocy es a e
one o he majo cell ypes p oducing choles e ol, and inc eased choles e ol
biosyn hesis has also been ound in o ganoids om indi iduals ca ying Tau mu a ions
(6), sugges ing ha pe u bed choles e ol me abolism is a common pa hway and ea ly
e en in he e iology o AD. Besides, APOE4 as ocy es show inc eased in lamma o y
esponses compa ed o APOE3 as ocy es (5). A ecen s udy desc ibes an
exace ba ed p oin lamma o y s a e on APOE4 as ocy es associa ed wi h T ansgelin
3 (TAGLN3) down egula ion and NF-kB ac i a ion (7). In e es ingly, his s a e can be
pha macologically e e ed by TAGLN3 supplemen a ion, highligh ing TAGLN3 as a
a ge o modula e in lamma ion in APOE4 as ocy es. Impo an ly, imbalances a cell-
au onomous le el also a ec as ocy e-neu on communica ion. When co-cul u ed wi h
neu ons, APOE4 as ocy es p o ide less suppo o neu onal su i al and
synap ogenesis (8). Mo eo e , in o ganoids composed by ei he APOE3 o APOE4
neu ons and as ocy es he e is inc eased APOE4-dependen synapse loss,
neu odegene a ion and Tau pa hology (4,9).
As ocy e-mic oglia c oss alk also has an impac on AD-associa ed in lamma o y
p ocesses. In i-cul u e sys ems wi h heal hy hiPSC-de i ed as ocy es, neu ons and
mic oglia, he complemen p o ein C3, which is ele a ed in b ains o AD pa ien s and
in ol ed in neu odegene a ion, inc eases unde in lamma o y condi ions due o
as ocy e-mic oglia ecip ocal signaling ha induces hem o o e p oduce C3.
As ocy ic p oduc ion o C3 induced by mic oglia, as well as mic oglial p oduc ion o
C3 e-induced by as ocy es a e u he enhanced in AD i-cul u es de i ed om
hiPSCs ha bo ing he APPSWE mu a ion (10). Ano he 3D i-cul u e AD model ha
de elops Aβ pa hology and Tau accumula ion shows ha as ocy e-sec e ed
in e leukin-3 (IL-3) ep og ams mic oglia a molecula , mo phological and unc ional
le els. Rep og ammed mic oglia acqui e an acu e immune esponse, inc eased
mo ili y and enhanced capaci y o clus e and clea Aβ and Tau agg ega es es ic ing
AD pa hology (11). As ocy es sec e e o he in lamma o y ac o s and molecules
po en ially in ol ed in hei c oss alk wi h mic oglia, neu ons and o he b ain cells.
hiPSC-based in i o sys ems a e bes sui ed o modeling he in lamma o y axis
be ween hese cells, dissec ing he ole o as ocy es in complex AD cellula
en i onmen s and hei impac on neu odegene a ion in AD. Mo eo e , hese models
cons i u e a powe ul app oach o iden i ying key compounds and main molecula
playe s enabling he de elopmen o as ocy e a ge ing he apeu ic s a egies.
In summa y, human as ocy es ge dys unc ional a ea ly s ages o AD and agg a a e
he pa hology a ec ing majo p ocesses including Aβ p oduc ion/clea ance,
choles e ol/lipid me abolism, oxida i e s ess and calcium dynamics. Mo eo e , in AD,
human as ocy es lose hei homeos a ic unc ions p o iding less suppo o synapses
and neu ons, while closely in e ac ing wi h mic oglia, being key media o s o
neu oin lamma ion. No el he apeu ic s a egies a ge ing as ocy es should aim a
enhancing hei neu o ophic/neu op o ec i e p ope ies, modula ing hei immune
esponses, and e e sing hei lipid/choles e ol me abolic al e a ions, oxida i e s ess
and calcium dys unc ion. Nex -gene a ion hiPSC-based app oaches should include as
well in i o analyses o human as ocy es ansplan ed in chime ic AD mice (12).
Chime as o e a unique oppo uni y o analyze human as ocy e dys unc ion in he li e
AD b ain and how i con ibu es o AD p og ession. Combina ion o in i o and in i o
models wi h CRISPR-Cas9 edi ing o allow a ge ing speci ic AD isk genes o a ian s
in human as ocy es, ansc ip omics and high- esolu ion imaging will be c i ical o
u he explo ing he ole o human as ocy es in AD, and i will open new a enues
enabling he de elopmen o as ocy e-speci ic a ge ing he apeu ics o p e en , slow
down and e en cu e AD.
Lis o abb e ia ions:
CNS: Cen al ne ous sys em; AD: Alzheime ’ s disease; GWAS: Genome-wide
associa ion s udies; LOAD: la e-onse AD; hiPSC: human induced plu ipo en s em
cells; Aβ: β-amyloid; ROS: eac i e oxygen species; apoE: apolipop o ein E; TAGLN3:
T ansgelin 3; IL-3: in e leukin-3.
Decla a ions:
E hics app o al and consen o pa icipa e
No applicable.
Consen o publica ion
No applicable.
A ailabili y o da a and ma e ials
No applicable.
Compe ing in e es s
The au ho s decla e ha hey ha e no compe ing in e es s.
Funding
JTCW ecei ed unding om NIH NIA K01AG062683, 1R56AG078733, To le Schola
Awa d and B igh Focus Founda ion (A2022049S). AMA ecei es unding om he
MCIN/AEI/10.13039/501100011033/FEDER (RTI2018-101850-A-I00, RYC2020-
029494-I, and PID2021-125443OB-100 g an s), he Alzheime ’s Associa ion (AARG-
21-850389 g an ), he Basque Go e nmen (PIBA-2020-1-0030 g an ), and
IKERBASQUE; and is he ecipien o an IBRO Ea ly Ca ee Awa d.
Au ho s' con ibu ions
JTCW and AMA w o e he i s e sion o he manusc ip and e ised i . JTCW and
AMA p epa ed he igu e. Bo h au ho s ead and app o ed he inal manusc ip .
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Figu e 1. Human as ocy es ge dys unc ional a ea ly s ages o AD and exace ba e
he pa hology a ec ing majo AD p ocesses. Combina ion o hiPSC-based in i o
and in i o models wi h gene edi ing, ansc ip omics and high- esolu ion imaging will
allow in dep h analyses o human as ocy es in AD and enable he de elopmen o
as ocy e a ge ing he apeu ics.
