Sha ed molecula signa u e in Alzheime ’s disease and schizoph enia: A
sys ema ic e iew o he eelin signaling pa hway
Ana Isabel Valde ama-Man illa
c,1
, Celia Ma ín-Cue as
a,b,1,*
, Ana G´
omez-Ga ido
a,b
,
C is ina Mo en e-Mon illa
a
, Benedic o C espo-Faco o
a,b,c
, Susana Ga cía-Ce o
a,b
a
Ins i u o de Biomedicina de Se illa (IBiS)/Uni e si y Hospi al Vi gen del Rocío/CSIC/Uni e si y o Se illa, Manuel Siu o AV, Se ille 41013, Spain
b
Spanish Ne wo k o Resea ch in Men al Heal h (CIBERSAM, ISCIII), Mon o e de Lemos AV, 3-5, Mad id 28029, Spain
c
Depa men o Psychia y, School o Medicine, Uni e si y o Se ille, Manuel Siu o AV, Se ille 41013, Spain
ARTICLE INFO
Keywo ds:
Reelin
RELN
APOER2
DAB1
Schizoph enia
Alzheime ’s disease
ABSTRACT
The Reelin signaling pa hway, pa icula ly he RELN-APOER2-DAB1 complex, has eme ged as a key con ibu o
o he neu opa hology o Alzheime ’s disease (AD) and Schizoph enia (SZ). Despi e being dis inc clinical con-
di ions, hese diso de s exhibi simila pa e ns o cogni i e decline, including ea ly dis up ions in synap ic
unc ion and memo y impai men s. No ably, indi iduals wi h SZ ha e a 2–4 old inc eased isk o de eloping AD
o o he demen ias, highligh ing po en ial sha ed molecula mechanisms, and posi ioning Reelin as a pi o al link
be ween hem. This sys ema ic e iew explo es he ole o Reelin and i s signaling componen s ac oss hese
diso de s. In AD, Reelin dis up ion co ela es wi h hallma k ea u es such as Tau hype phospho yla ion,
amyloid-be a accumula ion, and cogni i e de ici s. In SZ, al e a ions in Reelin signaling, including epigene ic
modi ica ions a ec ing RELN exp ession, a e linked o dis up ions in neu onal de elopmen and synap ic plas-
ici y, pa icula ly in he pa ie al and p e on al co ices. Addi ionally, genomic s udies e eal speci ic RELN
a ian s and allelic imbalances ha may in luence disease se e i y and ea men esponse in SZ, sugges ing
RELN’s ole as a po en ial bioma ke o he apeu ic ou comes. Region-speci ic Reelin al e a ions in bo h AD and
SZ sugges di e ing impac s ye unde sco e a po en ial common molecula o igin. Ou indings highligh he
Reelin pa hway as a molecula con e gence poin , wa an ing u he in es iga ion as a he apeu ic and diag-
nos ic a ge o AD, SZ, and po en ially o he neu opsychia ic diso de s. The in e play be ween gene ic and
epigene ic egula ion o RELN may p o ide no el insigh s in o neu odegene a ion, wi h implica ions o
pe sonalized in e en ion s a egies in AD and SZ.
1. In oduc ion
Reelin, an ex acellula ma ix glycop o ein encoded by he RELN
gene on ch omosome 7q22, plays a i al ole in neu ode elopmen and
he main enance o adul cen al ne ous sys em (CNS) unc ions
(Bo ella-L´
opez e al., 2006;Jossin, 2020;Ha o i and Kohno, 2021;
Alexande e al., 2023). Du ing ea ly b ain de elopmen , Reelin egu-
la es c i ical p ocesses such as neu onal mig a ion and b ain s uc u e
o ma ion, ensu ing p ope o ganiza ion o neu al ci cui s (Jossin, 2020;
Ha o i and Kohno, 2021). In adul hood, Reelin con inues o suppo
synap ic plas ici y, dend i ic g ow h, spine o ma ion, and synap o-
genesis, all o which a e essen ial o main aining cogni i e unc ion and
neu al s abili y (Wasse and He z, 2017; Yamakage e al., 2019; Jossin,
2020; S´
anchez-Hidalgo e al., 2022; Alexande e al., 2023). These dy-
namic oles highligh Reelin’s dual impo ance in bo h neu o-
de elopmen al p ocesses and he li elong main enance o synap ic
in eg i y.
Reelin unde goes p o eoly ic p ocessing (Fig. 1) and exe s i s bio-
logical e ec s by binding o i s p ima y ecep o s: Apolipop o ein E
ecep o 2 (APOER2) and he Ve y low-densi y lipop o ein ecep o
(VLDLR) (Hiesbe ge e al., 1999; Bosch e al., 2016; Ogino e al., 2017;
Wasse and He z, 2017; Alexande e al., 2023). This in e ac ion igge s
in acellula signaling pa hways h ough he phospho yla ion o
Disabled homolog-1 (DAB1) by S c amily y osine kinases, egula ing
* Co espondence o: Hospi al Uni e si a io Vi gen del Rocío, A da. Manuel Siu o s/n, Se illa 41013, Spain.
E-mail add esses: [email p o ec ed] (A.I. Valde ama-Man illa), [email p o ec ed] (C. Ma ín-Cue as), [email p o ec ed] (A. G´
omez-Ga ido),
[email p o ec ed] (C. Mo en e-Mon illa), [email p o ec ed] (B. C espo-Faco o), [email p o ec ed] (S. Ga cía-Ce o).
1
These au ho s ha e con ibu ed equally o his wo k and sha e i s au ho ship.
Con en s lis s a ailable a ScienceDi ec
Neu oscience and Biobeha io al Re iews
jou nal homepage: www.else ie .com/loca e/neubio e
h ps://doi.o g/10.1016/j.neubio e .2025.106032
Recei ed 23 Decembe 2024; Recei ed in e ised o m 21 Janua y 2025; Accep ed 26 Janua y 2025
Neu oscience and Biobeha io al Re iews 169 (2025) 106032
A ailable online 31 Janua y 2025
0149-7634/© 2025 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY license ( h p://c ea i ecommons.o g/licenses/by/4.0/ ).
neu onal in eg i y, synap ic de elopmen , and Tau p o ein phospho y-
la ion (Rice e al., 1998; Hiesbe ge e al., 1999; Wasse and He z, 2017;
Ha o i and Kohno, 2021). Dys egula ion o his pa hway is linked o
auopa hies, including Alzheime ’s disease (AD), whe e abno mal Tau
phospho yla ion con ibu es o neu odegene a ion (Bock e al., 2004;
Jossin e al., 2007; Alexande e al., 2023, Yi e al., 2024). Addi ionally,
Reelin also in e ac s wi h memb ane in eg ins (Sekine e al., 2012) and
amyloid p ecu so p o ein (APP) (He z and Chen, 2006; McCo kindale
e al., 2022; Alexande e al., 2023), in luencing neu onal mig a ion, and
amyloid p ocessing (He z and Chen, 2006; McCo kindale e al., 2022).
Dis up ions in hese mechanisms a e di ec ly linked o he o ma ion o
amyloid-be a plaques (Selkoe, 2000; He z and Chen, 2006; Alexande
e al., 2023), a hallma k o AD. Consequen ly, hese indings posi ion
Reelin as a c i ical a ge o unde s anding and po en ially ea ing
neu odegene a i e diseases such as AD (Selkoe, 2000; He z and Chen,
2006; McCo kindale e al., 2022; Alexande e al., 2023; Lope a e al.,
2023).
Reelin’s dys unc ion is also associa ed wi h neu opsychia ic diso -
de s like Schizoph enia (SZ) and bipola diso de (BD) (Impagna iello
e al., 1998; Guido i e al., 2000a.; Selkoe, 2000; He z and Chen, 2006;
S´
anchez-Hidalgo e al., 2022; Wa en e al., 2024). Pos -mo em s udies
ha e e ealed educed Reelin exp ession in key b ain egions, including
he p e on al co ex, hippocampus, and cauda e nucleus, in indi iduals
wi h SZ (Impagna iello e al., 1998; Guido i e al., 2000b; Fa emi e al.,
2005; Eas wood and Ha ison, 2006; Imai e al., 2017; A ioka e al.,
2018; Ma zan e al., 2021; Alexande e al., 2023). This hypo unc ion is
hough o dis up GABAe gic signalling and impai NMDA ecep o
unc ion, con ibu ing o an imbalance in exci a o y-inhibi o y (E/I)
signalling, a hallma k o SC6Z pa hology (Gue in e al., 2021;
S´
anchez-Hidalgo e al., 2022; Gillespie e al., 2024).
Clinically, SZ and AD sha e o e lapping ea u es despi e being
dis inc diso de s, wi h he mechanisms linking hese condi ions
emaining la gely unexplo ed (Whi e and Cummings, 1996). Bo h a e
cha ac e ized by signi ican cogni i e impai men s, s uc u al and
unc ional abno mali ies in b ain egions such as he hippocampus, and
p og essi e declines in neu al unc ion (DeCa olis and Eisch, 2010).
No ably, indi iduals wi h SZ a e a a 2–4 old inc eased isk o de el-
oping AD o o he demen ias la e in li e (Kochuno e al., 2021),
unde sco ing a po en ial ela ionship be ween hese wo condi ions.
Adding o his clinical o e lap, psycho ic symp oms such as hallucina-
ions and delusions, adi ionally associa ed wi h SZ, a e also epo ed in
40 %–60 % o AD pa ien s. Eme ging gene ic e idence u he suppo s
his connec ion, wi h ecen s udies iden i ying 65 genes common o
bo h SZ and AD, including he RELN gene (Guo e al., 2024). Toge he ,
his sha ed molecula amewo k, combined wi h he no ed clinical
con e gence, s eng hen he hypo hesis ha simila neu opa hological
pa hways may unde lie bo h diso de s. In his con ex , he concep o
"accele a ed aging" has been p oposed o accoun o he clinical, bio-
logical, and unc ional decline obse ed in SZ, echoing Emil K aepelin’s
o iginal desc ip ion o he diso de as "demen ia p aecox" (Ki kpa ick
e al., 2008). This phenomenon aligns wi h he cogni i e and s uc u al
b ain changes sha ed by SZ and AD, sugges ing a con e gence o neu-
ode elopmen al and neu odegene a i e p ocesses.
Gi en Reelin’s cen al ole in bo h neu ode elopmen and synap ic
unc ion, and i s in ol emen in neu opsychia ic and neu odegene a-
i e diso de s, his p o ein could se e as a uni ying ac o in unde -
s anding he neu opa hology o SZ and AD. Consequen ly, his
sys ema ic e iew aims o explo e he po en ial link be ween SZ and AD
h ough a comp ehensi e analysis o Reelin exp ession in human sam-
ples, including pos mo em s udies and gene ic models, emphasizing he
ole o he RELN-APOER2-DAB1 signaling pa hway and gene ic a ian s
o he RELN gene in he pa hogenesis o bo h clinical condi ions (Fig. 2).
2. Me hod
A sys ema ic e iew was conduc ed ollowing he P e e ed Repo -
ing I ems o Sys ema ic Re iews and Me a-analyses (PRISMA) s a e-
men (Mohe e al., 2009) and a p o ocol was egis e ed in PROSPERO
(CRD42024596895).
2.1. Sea ch s a egy
Medical Subjec Headings (MeSH) e ms we e used o selec he mos
ele an keywo ds o he sea ch. The ollowing sea ch s a egy was
employed in PubMed and Scopus da abases: ((Reelin) OR (RELN) OR
(DAB1)) AND ((Alzheime ) OR (Schizoph enia) OR (neu opsychia ic
diso de s)). The sea ch was conduc ed in Decembe 2023. A icles
included in he analysis ocused on he in ol emen o Reelin and o he
componen s o i s signaling pa hway, such as APOER2,DAB1 and
ADAMTS2 and 3, in he neu opa hogenesis o AD and SZ in humans
(pos mo em issue, ce eb ospinal luid (CSF), pe iphe al blood, sali a).
The a icles we e e alua ed by wo independen e iewe s. We also
made a c oss- e e ence sea ch o included ele an s udies and p e ious
e iews and con ac ed s udy au ho s and expe s o da a cla i ica ion.
Fig. 1. Reelin s uc u e and p o eoly ic p ocessing. The Reelin p o ein consis s o h ee dis inc egions: N- e minal, cen al, and C- e minal domains, sepa a ed by
clea age si es (Jossin e al., 2004, 2007; Jossin, 2020; Ha o i and Kohno, 2021) ha a e igh ly egula ed by p o eoly ic enzymes such as me allop o einases,
including a disin eg in and me allop o einase wi h h ombospondin mo i s (ADAMTS) (Jossin e al., 2004; Jossin, 2020; Ha o i and Kohno, 2021). C ea ed wi h
Bio ende .com.
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
2
2.2. Eligibili y
Inclusion c i e ia we e selec ed o sys ema ize he sea ch in he da-
abases so ha only a icles o in e es on he ole o Reelin in neu o-
psychia ic diso de s in humans would be ob ained. These inclusion
c i e ia we e s udies on (i) he ole o Reelin, i s gene RELN, o i s
in e media y DAB1 in AD and SZ, (ii) s udies in ol ing human subjec s,
(iii) clinical ials, (i ) s udies wi h case-con ol compa isons and ( )
me a-analyses, wi h he goal o ex ac ing addi ional ele an a icles
om hei e e ences. Exclusion c i e ia we e (i) e iews and sys ema ic
e iews, (ii) psychia ic diso de s o he han AD and SZ, excluding
con en ela ed o o he diso de s in ol ing Reelin such as dep ession,
epilepsy, au ism spec um diso de (ASD), o BD, (iii) s udies using
animal samples o based on animal models, (i ) s udies ha do no
include Reelin, i s gene RELN, o i s in e media y DAB1 as a p ima y
ocus in AD o SZ and ( ) a icles published be o e 2010.
2.3. S udy selec ion
Two independen e iewe s (AIV-M and CM-C) sc eened he i les
and abs ac s o iden i y s udies ha me he inclusion c i e ia ou lined
abo e using Rayyan (Ouzzani e al., 2016) so wa e. The same e-
sea che s hen e iewed he eligible ull ex s. The inal lis o a icles
was ag eed o by consensus. Disag eemen s on eligibili y we e esol ed
by discussions wi h wo addi ional e iewe s (BC-F and SG-C).
2.4. Da a ex ac ion, syn hesis, and quali y assessmen
The ollowing in o ma ion was ex ac ed in iplica e om each
s udy: i s au ho , yea , ype o s udy and sample, s udy a ge , s udy
subjec s, clinical a iables included, esul s and main indings.
O he hi y-se en included s udies, hi y-six we e e alua ed using
he checklis de eloped by he Cla i y g oup a McMas e Uni e si y
(A ailable online: h p://www.dis ille s .com/wp-con en /uploads/20
21/03/Tool- o-Assess-Risk-o -Bias-in-Case-Con ol-S udies-Dis ille SR.
pd ). This checklis is designed o assess he isk o bias in case-con ol
s udies ac oss i e key domains: he quali y o exposu e assessmen ,
con idence ha cases had de eloped he ou come o in e es , app o-
p ia e selec ion o cases, app op ia e selec ion o con ols, and app o-
p ia e ma ching o cases and con ols based on signi ican p ognos ic
a iables o s a is ical adjus men s. Each s udy was classi ied in o one o
ou ca ego ies o each domain: low isk o bias, p obably low isk o
bias, p obably high isk o bias, o de ini ely high isk o bias (Figu e S1).
The emaining s udy, a me a-analysis conduc ed by Hui Gao e al.
(2015), u ilized he Newcas le-O awa Scale (NOS) (Wells e al., 2009)
o quali y assessmen . The NOS applies a “s a ” a ing sys em o e al-
ua e he me hodological quali y ac oss h ee a eas: selec ion, compa-
abili y, and exposu e. The sco es on he NOS ange om ze o
(indica ing low quali y) o nine s a s (indica ing high quali y). S udies
ha sco ed ewe han 5 s a s we e classi ied as “low quali y,”while
hose wi h 5 o mo e s a s we e conside ed “high quali y.”The
Supplemen a y Ma e ial was used o addi ional da a and au ho s we e
con ac ed o eques addi ional in o ma ion.
3. Resul s
3.1. Da a analysis: s udies included and excluded
A o al o 1855 a icles we e e ie ed om he da abases (PubMed
and Scopus). O hese, 131 duplica e e e ences ound by c oss-
e e encing, 3 me a-analyses and 431 e iews we e excluded. F om
he emaining s udies, 1261 mo e we e excluded o he ollowing ea-
sons: o he psychia ic diso de s (no AD o SZ) (227 a icles), animal
models s udies (428), s udies no ocused on Reelin (220) and published
p io o 2010 (386). Addi ionally, 95 a icles we e e ie ed om 3
me a-analyses, o which 16 we e excluded as duplica e e e ences, and
71 s udies we e excluded o he ollowing easons: o he psychia ic
diso de s (no AD o SZ) (17 a icles), animal models s udies (0), s udies
no ocused on Reelin (22) and published p io o 2010 (32). The
emaining 37 s udies we e included in he inal analysis (Fig. 3).
3.2. Risk o bias
The me hodological quali y o he included s udies was assessed
using he checklis p o ided by he Cla i y g oup a McMas e Uni e si y
(Figu e S1). O he hi y-six s udies e alua ed wi h his scale, ou did
no speci y he diagnos ic c i e ia used o de e mine he de elopmen o
he ou come o in e es (Maloku e al., 2010; Liu e al., 2010; O adia and
Shi man, 2011; Abe g e al., 2014). Six s udies epo ed ha cases we e
selec ed om a de ined ca chmen a ea whe e diagnos ic p ocedu es
we e likely o ha e changed o e ime (Kuang e al., 2011; B¨
onsch e al.,
2012; Abe g e al., 2014; Feh´
e e al., 2015; Ho e al., 2020; Nie e al.,
2021). Eigh s udies indica ed ha con ols we e selec ed om a
di e en popula ion han he cases (Liu e al., 2010; Kuang e al., 2011;
B¨
onsch e al., 2012; Abe g e al., 2014; Feh´
e e al., 2015; Nabil Fik i
e al., 2017; Xu e al., 2020; Nie e al., 2021).
Twen y- i e s udies did no employ any me hod o con ol he case-
con ol g oups o demog aphic ea u es o clinical cha ac e is ics (e.g.,
age and sex) (Wedenoja e al., 2010; Liu e al., 2010; O adia and Shi -
man, 2011; An oniades e al., 2011; Kuang e al., 2011; Ve b ugghe
e al., 2012; B¨
onsch e al., 2012;No e and Knuesel, 2013;Cuchil-
lo-Ib´
a˜
nez e al., 2013;Abe g e al., 2014;Dong e al., 2015;Feh´
e e al.,
2015;Cuchillo-Ib´
a˜
nez e al., 2016;Ma a-Balague e al., 2018;Han
e al., 2019;L´
opez-Fon e al., 2019;Sozuguzel e al., 2019;Bai e al.,
2019;Xu e al., 2020;Lid´
on e al., 2020;Nie e al., 2021;Ramsden e al.,
2022;B ache -Smi h e al., 2022;Lope a e al., 2023;Ramsden e al.,
2023). Six een s udies we e classi ied as ha ing a low isk o bias, wi h
all domains a ed as “g een”o wi h only one domain a ed as “yellow”
(Li e al., 2011; K ame e al., 2011; Habl e al., 2012;No e and
Knuesel, 2013;Bu ill e al., 2015;Ho nig e al., 2015;Dong e al., 2015;
Nabil Fik i e al., 2017;Luo e al., 2019;L´
opez-Fon e al., 2019;Bai
e al., 2019;Ho e al., 2020;Zhou e al., 2022;Ramsden e al., 2022;
Fig. 2. G aphical abs ac o his e iew. C ea ed wi h Bio ende .com.
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
3
L´
opez-Fon e al., 2022;Ramsden e al., 2023). Twel e s udies showed
an unclea isk o bias, wi h one domain a ed as “ ed”o wo domains
a ed as “yellow”(Maloku e al., 2010; Wedenoja e al., 2010; An o-
niades e al., 2011; Ve b ugghe e al., 2012; Cuchillo-Ib´
a˜
nez e al., 2013;
Cuchillo-Ib´
a˜
nez e al., 2016;Ma a-Balague e al., 2018;Han e al.,
2019;Sozuguzel e al., 2019;Lid´
on e al., 2020;B ache -Smi h e al.,
2022;Lope a e al., 2023). Eigh s udies we e assessed as ha ing a high
isk o bias, wi h wo domains a ed as “ ed”o h ee o mo e domains
a ed as “yellow”o “ ed”(Liu e al., 2010; O adia and Shi man, 2011;
Kuang e al., 2011; B¨
onsch e al., 2012; Abe g e al., 2014; Feh´
e e al.,
2015; Xu e al., 2020; Nie e al., 2021). Ou isk o bias analysis ca e-
go ized s udies om ca ego ies B and C as ha ing an “unclea ” isk o
bias (yellow ca ego y).
The me a-analysis by Hui Gao e al. (2015) iden i ied se e al biases
using he NOS scale. In he selec ion domain, he e was a isk o bias due
o he lack o speci ied c i e ia o de ining cases and con ols and un-
ce ain y ega ding whe he pa icipan s adequa ely ep esen ed he
a ge popula ion. Fo compa abili y, s udies employed s a is ical ad-
jus men s o co a ia es such as age and sex, educing he isk o bias by
con olling o con ounding ac o s. In e ms o exposu e and ou come
assessmen , s anda dized measu emen me hods we e used, which
dec eased he isk o bias. Howe e , he non- esponse a e among case
and con ol g oups was no e alua ed. Consequen ly, hese biases in he
indi idual s udies included in he me a-analysis could accumula e and
po en ially dis o he o e all conclusions, a ec ing he alidi y and
applicabili y o he inal esul s.
3.3. Role o he Reelin signaling pa hway in AD
Li e a u e included in his sys ema ic e iew cen e ed on he ole o
he Reelin signaling pa hway in AD is epo ed in Table 1. Pos mo em
s udies ha e indica ed ha ea ly-s age accumula ion o phospho yla ed
Tau (pTau) in AD is closely linked o he dis up ion o he APOER2-DAB1
pa hway, which is highly associa ed wi h Reelin signaling, occu ing
ac oss a ious neu oana omical egions, pa icula ly in he en o hinal-
hippocampal a eas (Ramsden e al., 2023). This dis up ion is belie ed
o accele a e neu odegene a ion and disease p og ession, exace ba ing
memo y de ici s and p omo ing Tau hype phospho yla ion, a key ac o
in AD pa hology (Ramsden e al., 2022, 2023). Simila ly, neu onal
popula ions ulne able o AD show high APOER2 p o ein and gene
exp ession, which is hough o con ibu e o he o ma ion o neu i ic
plaques (Ramsden e al., 2022, 2023,Table 1). Addi ionally, lipid pe -
oxida ion o he APOER2-DAB1 pa hway has also been associa ed wi h
AD p og ession (Ramsden e al., 2022, 2023; Yi e al., 2024).
An epis a ic in e ac ion be ween APOE and he RELN-DAB1 pa hway
has also been iden i ied, highligh ing he impo ance o his pa hway in
AD neu opa hogenesis (B ache -Smi h e al., 2022). New signi ican loci
ac oss he AD genome, including hose mapping o DAB1, u he sup-
po he connec ion be ween he RELN-DAB1 pa hway and AD. Speci -
ically, single nucleo ide polymo phisms (SNPs) RELN- s528528 and
RELN- s607755 we e associa ed wi h AD isk in men bu no women,
sugges ing a sex-speci ic gene ic p edisposi ion o AD (Feh´
e e al.,
2015). Inc eased DAB1 mRNA exp ession in he human do sola e al
p e on al co ex has also been linked o p o ec ion agains AD (Gao
e al., 2015), while DAB1-exon 22 C/G ( s362691) has been signi ican ly
associa ed wi h AD neu opa hogenesis (An oniades e al., 2011). These
indings emphasize he complexi y o gene ic ac o s in ol ed in AD and
he c i ical ole o he RELN-DAB1 pa hway in i s pa hology (An oniades
e al., 2011). Likewise, associa ions be ween a ious geno ypes in he
Reelin signaling pa hway and AD isk ha e also been iden i ied, wi h
isk SNPs such as RELN- s2299356 and p o ec i e SNPs like
RELN- s528528, PLK2-RS15009, PLK2- s702723, and CAMK2A
( s3756577 and s3822606), unde sco ing he pa hway’s signi icance in
he disease (Bu ill e al., 2015).
Fu he mo e, pa ien s wi h spo adic AD exhibi ed lowe p o ein
le els o APOER2 in CSF and a highe Reelin/APOER2 a io (L´
opez-Fon
Fig. 3. PRISMA low diag am o he e iewing p ocess –sys ema ic selec ion o inclusion o exclusion. C ea ed wi h Bio ende .com.
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
4
Table 1
Main indings o s udies on he ole o Reelin signaling pa hway in Alzheime ’s Disease.
Fi s au ho
and yea
Type o s udy and
sample
S udy a ge S udy subjec s Clinical a iables
included
Resul s Main indings
Lope a e al.
(2023)
Gene ic s udy. S udy o he second case
in he wo ld wi h p o en
ex eme esis ance o
au osomal dominan AD.
Male wi h
esilience o
AD.
Male emains ee o
AD symp oms un il he
age o 67, despi e
ca ying a mu a ion
(PSEN1-E280A) o
high isk o AD, a e y
high load o amyloid
plaque and en o hinal
Tau angles.
●Resis ance o he
de elopmen o AD despi e
he isk mu a ion is linked
o a a ian o RELN called
COLBOS.
●COLBOS binds o VLDLR
and APOER2 ecep o s.
●I is in ol ed in a gain o
unc ion, wi h an inc eased
abili y o ac i a e DAB1
and educe human Tau
phospho yla ion.
The RELN COLBOS
a ian ha con e s
esis ance o he onse o
ea ly AD symp oms in
he high- isk mu a ion
pa ien sugges s a ole
o RELN signaling
pa hways in esis ance
o demen ia.
Ramsden e al.
(2023)
Pos mo em issue and
pe iphe al blood in
i o. APOER2
exp ession and
accumula ion o
APOER2-DAB1
pa hways componen s.
Samples aken om
amygdala, hippocampus
and medial empo al
gy us.
S udy o he componen s
o he APOER2-DAB1 and
RELN-DAB1 pa hway in
he neu opa hogenesis o
AD.
64 apid
au opsy cases.
Clinic-pa hological
spec um o AD.
Diagnosis acco ding o
NIA-Reagan c i e ia.
Includes pos mo em
in e al, B aak s ages,
Thal s ages. Cogni i e
assessmen c i e ia:
MiniMen al S a us
Exam MMSE, 0.30.
pTau is one o many
componen s o he
APOER2-DAB1 pa hway
ha accumula e in
mul iple neu oana omical
(en o hinal-hippocampal)
loca ions in he ea ly
s ages o AD de elopmen .
I suppo s he concep ha
dis up ion o APOER2-
DAB1 enables AD
neu odegene a ion and
disease p og ession.
●APOER2-DAB1
signaling supp esses Tau
phospho yla ion.
●Popula ions o
ulne able neu ons
s ongly exp ess
APOER2.
●Mul iple componen s
o he APOER2-DAB1
pa hway accumula e
leading o neu i ic
plaques. They co ela e
wi h disease
p og ession.
●In e media es o he
RELN-DAB1 pa hway
accumula e in neu ons
ha exp ess APOER2
ex acellula ly, o ming
plaques.
B ache -Smi h
e al. (2022)
Gene ic s udy. S udy o
ApoE4 homozygous
indi iduals. Samples
om he UK Biobank.
To iden i y i ApoE4
ca ie s ha e o he
gene ic p edisposing
ac o s in he p og ession
o AD.
5390
indi iduals.
288 cases and
5102 con ols.
●Subjec s olde han
65 yea s homozygous
o ApoE4.
●Pa ien s wi h sex
ch omosome
aneuploidy a e
excluded.
●The con ol g oup is
ob ained om subjec s
who a e nega i e o
AD bu posi i e o
o he demen ias.
The DAB1-RELN pa hway
is closely ela ed o ApoE
exp ession and he e o e
di ec ly in ol ed in he
neu opa hogenesis o AD.
●No signi ican SNP
associa ions a e ound a
he ApoE locus wi h AD.
●New signi ican loci
a e iden i ied
h oughou he AD
genome by mapping
DAB1.
●The DAB1-RELN
pa hway is associa ed
wi h AD.
●The e is an epis a ic
in e ac ion be ween
ApoE and he DAB1-
RELN pa hway.
L´
opez-Fon e al.
(2022)
CSF. To assess whe he
p o eoly ic agmen s o
Reelin a e a ec ed in CSF
in AD.
43 cases e sus
14 con ols.
Di e en ia ion
acco ding o sex, age
(79 yea s) and
mu a ed ApoE s a us.
●Dec eased Reelin leng h
o 420 kDa.
●310 kDa N- e minal
inc ease in AD pa ien s due
o C si e excision.
●500 kDa abe an Reelin
species in AD.
Appea ance o abe an
Reelin in AD subjec s
sugges s he
in ol emen o Reelin in
AD.
Ramsden e al.
(2022)
Pos mo em issue. In
i o biochemical
expe imen s.
In ol emen o he
Reelin-APOER2-DAB1
pa hway in ana omical
ulne abili y o spo adic
AD.
26 pa ien s
e sus con ols.
Cogni i ely heal hy,
wi h mild cogni i e
impai men o
spo adic AD.
Di e ences in sex, age
and pos mo em
in e al. Cogni i e
assessmen acco ding
o MMSE.
●APOER2 is exp essed in
a eas o he en o hinal-
hippocampal pa hway
in ol ed in memo y.
●Reelin-APOER2-DAB1
and o he componen s o
he cascade a e exp essed
in neu i ic plaques in AD
cases.
●Ma ke s o he Reelin-
APOER2-DAB1 pa hway
a e associa ed wi h disease
p og ession and cogni i e
de ici s
The indings p o ide
in o ma ion o link lipid
pe oxida ion o APOER2
and componen s o he
Reelin-APOER2-DAB1
pa hway o ApoE
ecep o s in spo adic
AD.
Lid´
on e al.
(2020)
Pos mo em on al
co ex issue and CSF
samples om Hospi al
Clinic o Ba celona and
G¨
o ingen, Ge many.
To assess he po en ial
ole o CSF Reelin
exp ession as a diagnos ic
and p ognos ic me hod.
246
pos mo em
samples, o
which:
●AD N =55.
Samples a e andomly
dis ibu ed be ween
Ge many and Spain.
Heal hy subjec s, AD
and mild cogni i e
●Inc ease o RELN mRNA
in on al co ex in
ad anced s ages o AD. No
obse ed in s ages o mild
cogni i e impai men .
CSF Reelin mRNA le els
canno be conside ed a
diagnos ic me hod, bu
a e a p od omal ma ke
o AD.
(con inued on nex page)
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
5
Table 1 (con inued)
Fi s au ho
and yea
Type o s udy and
sample
S udy a ge S udy subjec s Clinical a iables
included
Resul s Main indings
●Mild
cogni i e
impai men
N=40.
●Con ols
N=41.
impai men a e
included.
●Dec eased le els o
Reelin in CSF in demen ia
pa ien s compa ed o
con ols.
Han e al. (2019) RNA sequencing o
pos mo em
hippocampal issue.
To iden i y he
associa ion o h ee exon
and SNP skipping e en s
o RELN and NOS1 genes
in AD, as well as hei
in ol emen in β-amyloid
accumula ion.
24 AD cases
e sus 50
cogni i ely
heal hy elde ly
con ols.
Ini ial age, sex and
yea s o educa ion.
Classi ica ion
acco ding o B aak
scale.
●Dec eased exp ession o
wo exons o RELN and one
o NOS1 in AD.
●The RELN SNP s362771
is ela ed o co ical
β-amyloid le els.
●This SNP is a egula o y
splicing elemen .
Exon skipping e en s
and SNPs ha impac
he splicing p ocess in
he human hippocampus
play a ole in he
pa hogenesis o AD by
pa icipa ing in he
accumula ion o
β-amyloid.
L´
opez-Fon e al.
(2019)
CSF sample. E alua ion o he
e iciency o Reelin
signaling in AD, ocusing
on he ela ionship
be ween Reelin and
APOER2 in CSF.
●Spo adic AD
N=14.
●Au osomal
Dominan
Alzheime ’s
Disease
(ADAD) N =7.
●Con ols
N=7.
Pa ien s wi h spo adic
AD and ADAD.
Di e en ia ion by age.
●Pa ien s wi h spo adic
AD exp ess lowe le els o
APOER2 in CSF and a
highe Reelin/APOER2
a io.
●ADAD ca ie s o PSEN1
mu a ions had highe
APOER2 le els and lowe
Reelin/APOER2 le els.
●APOER2 le els in CSF
may be a sui able
measu e o assess
al e ed Reelin signaling
in AD.
●Di e ences in Reelin
exp ession be ween
spo adic AD and ADAD.
Ma a-Balague
e al. (2018)
Pos mo em issue om
he Ins i u e o
Neu opa hology o
Ba celona.
To explo e he e ec o
β-amyloid (Aβ42) on DNA
me hyla ion o he RELN
p omo e a he C-
e minal end.
30 cases: 12
women and 18
men.
Pa ien s aged 75 ±10
yea s. They a e
classi ied acco ding o
B aak s age.
●Aβ42 dec eases DNA
me hyl ans e ase le els.
●Me hyla ion o he RELN
p omo e does no change
wi h Aβ42 adminis a ion.
●APOER2 le els a e
ound o be lowe a e
Aβ42.
●Aβ42-induced Reelin
signaling is associa ed
wi h inc eased Reelin
exp ession in AD.
●APOER2 le els
dec ease while Reelin
le els inc ease.
●APOER2 exe s a
modula o y ole on
Reelin exp ession.
Cuchillo-Ib´
a˜
nez
e al. (2016)
Pos mo em issue.
F on al co ex.
S udy o he in e ac ion
be ween Reelin and
β-amyloid in he b ain.
Pa ien s in ad anced
s ages o AD acco ding
o he B aak
classi ica ion.
Di e ence by age and
sex.
●Reelin shows in e ac ion
wi h β-amyloid, especially
in la e s ages o AD.
●Inc eased Reelin, wi h
educed DAB1 and
APOER2 in e naliza ion.
●Reelin exp ession is
inc eased in AD, bu
in e ac ion wi h Aβ
hinde s i s unc ion.
●APOER2 agmen s in
CSF could be a measu e
o assess he e iciency
o Reelin signaling,
which is dec eased in
AD.
Gao e al. (2015) Gene ic s udy. Explo a ion o he gene ic
implica ions o AD and i s
biological pa hways.
17 genes a e
s udied in 3
independen
AD da ase s.
Caucasian popula ion. O he genes s udied, he
exp ession o DAB1 mRNA
in human do sola e al
p e on al co ex s ood
ou .
●High exp ession o
DAB1 mRNA in he
p e on al co ex is
associa ed wi h
p o ec ion agains he
de elopmen o AD.
Bu ill e al.
(2015)
Pe iphe al blood
sample.
In ol emen o he Reelin
pa hway in he isk o
de eloping AD o mild
cogni i e impai men
(MCI).
●AD N =121.
●MCI N =94.
●Con ols
N=198.
40 SNP a ian s in 8
genes ela ed o he
RELN pa hway a e
geno yped in a Spanish
popula ion.
●Associa ion be ween
RELN ( s528528 and
s2299356), PLK2
( s15009 and s702723)
and CAMK2A ( s3756577
and s3822606) geno ypes
and AD is ound.
●RELN- s2299356
associa ion wi h AD isk.
●P o ec i e e ec o
RELN- s528528, PLK2-
s15009 and PLK2-
s702723 geno ype.
●CAMK2A- s756577
geno ype associa ed wi h
educed isk o AD.
●The e is a link
be ween ce ain
geno ypes o he Reelin
signaling pa hway, MCI
and AD.
●P o ec i e and isk
geno ypes wi hin he
RELN signaling pa hway
exis o AD.
Feh´
e e al.
(2015)
Gene ic s udy. Associa ion be ween
gene ic a ian s o RELN
and he isk o de eloping
AD.
432 cases wi h
308 con ols
om a
Hunga ian
popula ion.
Pa ien s wi h la e-
onse AD o 70 ±5
yea s a e included.
SNPs s528528 and
s607755 a e linked o AD
in men. No in women.
● s528528 and
s607755 a e associa ed
wi h AD isk,
speci ically in males.
No e and
Knuesel
(2013)
Pos mo em human
hippocampal issue and
CSF om he la e al
en icles.
In es iga ion in humans
o he al eady epo ed
age- ela ed educ ion o
Reelin in mice and i s
8 AD cases
e sus 8
con ols.
Indi iduals o he same
age and clinical s age
om he Ne he lands
B ain Bank,
●P esence o Reelin
agmen s con aining N-
and C- e mini in he
amyloid bodies (CAm),
●The p esence o
Reelin in CAm may be
linked o dis u bances in
neu onal anspo in
(con inued on nex page)
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
6
e al., 2022). In con as , ca ie s o p esenilin 1 (PSEN1) mu a ions
associa ed wi h au osomal dominan AD (ADAD) displayed highe
APOER2 p o ein le els and a lowe Reelin/APOER2 a io (L´
opez-Fon
e al., 2019). These indings sugges ha CSF APOER2 p o ein le els may
e lec al e a ions in Reelin signaling in AD, highligh ing di e ences in
p o ein exp ession be ween spo adic AD and ADAD (L´
opez-Fon e al.,
2022).
Rega ding al e a ions speci ically ela ed o Reelin, a ian s in i s
gen RELN, such as SNP s362771, ha e been linked o amyloid-be a
accumula ion (Han e al., 2019). Gene ic s udies ha e also e ealed
ha he RELN-COLBOS a ian , which binds o VLDLR and APOER2
ecep o s, is associa ed wi h esis ance o ea ly AD symp oms in in-
di iduals wi h high- isk mu a ions (Lope a e al., 2023). This COLBOS
a ian exhibi s a gain-o - unc ion e ec , enhancing DAB1 ac i a ion
and educing human Tau phospho yla ion (Lope a e al., 2023). These
indings unde sco e he c ucial ole o he Reelin signaling pa hway in
demen ia esis ance, pa icula ly in he con ex o gene ic isk ac o s o
AD. No ably, up egula ion o Reelin has also been obse ed as a
compensa o y esponse o s ess ela ed o Tau o amyloid-be a, e en
be o e he onse o demen ia symp oms, sugges ing ha Reelin may
se e as a p emo bid ma ke in AD (Cuchillo-Ib´
a˜
nez e al., 2013; Han
e al., 2019). In he same ein, inc eased p esence o N- and C- e mi-
nus-con aining Reelin agmen s has been de ec ed in co po a amylacea,
age- ela ed deposi s ound abundan ly in he molecula laye o he
hippocampus in AD pa ien s (No e and Knuesel, 2013). Al oge he ,
hese indings sugges ha al e a ions in Reelin may p ecede he
appea ance o demen ia symp oms in AD (K ame e al., 2011). Al e ed
RELN mRNA le els we e also no ed in CSF om AD pa ien s
(Cuchillo-Ib´
a˜
nez e al., 2016;Lid´
on e al., 2020). Finally, L´
opez-Fon
e al. (2022) showed a ma ked educ ion in he ull-leng h 420 kDa o m
o Reelin in AD compa ed o con ols, alongside a no able inc ease in he
N- e minal 310 kDa o m, a ibu ed o clea age a he C- e minal si e.
Addi ionally, an abe an 500 kDa o m o Reelin was also iden i ied in
AD pa ien s (L´
opez-Fon e al., 2022).
Rega ding epigene ic mechanisms, in i o adminis a ion o
amyloid-be a 42 led o dec eased le els o DNA me hyl ans e ase
(DNMT) (Ma a-Balague e al., 2018). In e es ingly, while RELN p o-
mo e me hyla ion emained una ec ed in AD b ain, APOER2 p o ein
and mRNA le els dec eased, and Reelin le els inc eased, suppo ing he
iew ha APOER2 could exe a modula o y ole on eelin exp ession
(Ma a-Balague e al., 2018). Addi ionally, Ma a-Balague e al. p opose
ha measu ing soluble N- e minal ApoER2 agmen s in CSF and
Table 1 (con inued)
Fi s au ho
and yea
Type o s udy and
sample
S udy a ge S udy subjec s Clinical a iables
included
Resul s Main indings
accumula ion in neu i ic
a icosi ies along he
ol ac o y limbic ac s.
Ams e dam a e
included.
sphe ical age- ela ed
deposi s.
●Inc eased densi y o
hese deposi s in he
hippocampal molecula
laye in AD.
he ageing p ocess,
esul ing in he
accumula ion o
me aboli es in neu i ic
a icosi ies.
●Aging changes in
Reelin le els could be
in ol ed in CAm
o ma ion by a ec ing
cy oskele on dynamics.
●The p esence o CAm
is an indica o o he
degene a i e s a e o
neu i ic compa men s.
Cuchillo-Ib´
a˜
nez
e al. (2013)
Pos mo em issue om
human on al co ex.
To de e mine whe he
β-amyloid-induced
al e a ion o Reelin will
lead o a signaling e o in
he Reelin pa hway,
con ibu ing o he
pa hogenesis o AD.
5 cases wi h AD
o 66 ±7 yea s
e sus 5
con ols o 73
±2 yea s.
UIPA Tissue Bank,
Mad id. Spo adic cases
o AD in B aak s ages
V-VI. Con ols wi hou
demen ia o b ain
pa hology. 73 ±2
yea s. Pos mo em
in e al 6 hou s.
● β-amyloid-induced
Reelin a ian s show a
educed abili y o
nega i ely egula e au
phospho yla ion ia
GSK3B and DAB1.
●I Reelin signaling is
de ec i e, he e is a
posi i e egula ion o he
14–3–3 p o ein ha d i es
au phospho yla ion
h ough modula ion o
GSK3B.
● β-amyloid-induced
Reelin species esul in a
educed abili y o bind
APOER2.
●Reelin in AD ails o
o m physiologically ac i e
dime s.
● β-amyloid induces he
exp ession o abno mal
Reelin species.
●I is he al e ed
exp ession o Reelin by
β-amyloid ha esul s in
a dis up ion o he
Reelin signaling
pa hway.
●Associa ion o
de egula ion o
β-amyloid and au
phospho yla ion
h ough Reelin.
●Reelin di ec ly
in ol ed in he
pa hogenesis o AD.
K ame e al.
(2011)
Pos mo em limbic and
neoco ical egion
issue.
Gene ic di e ences in
olde adul s wi h and
wi hou demen ia,
acco ding o
neu o ib illa y angle
(NFT) bu den.
299 non-
demen ed wi h
au opsy:
●185 wi h
high NFT
bu den.
●114 wi h low
NFT bu den.
●>65 yea s old.
●Deceased wi h
au opsy.
●Diagnosis o non-
demen ia.
●>1 clinical
assessmen wi hin 1
yea p io o dea h.
●DNA a ailable.
●Caucasian.
●Diagnosis o AD
acco ding o DSM-III-
R.
●Reelin signaling
pa hways a e in ol ed in
he phospho yla ion o au,
he main componen o
NFTs.
●Reelin is in ol ed in he
phospho yla ion o au
di ec ly o h ough
β-amyloid.
●RELN a ian s a e
ela ed o he
pa hogenesis o
cogni i e heal h.
●Posi i e egula ion o
Reelin could ep esen a
compensa o y esponse
o au- o β-amyloid-
linked s ess associa ed
wi h AD, e en be o e he
mani es a ion o
demen ia.
●Reelin p emo bid
ma ke .
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
7
in acellula C- e minal ApoER2 agmen s in on al co ex ex ac s
may se e as a eliable indica o o Reelin signaling impai men in pa-
ien s wi h AD.
3.4. Role o he Reelin signaling pa hway in SZ
S udies included in his sys ema ic e iew examining he ole o he
Reelin signaling pa hway in SZ a e summa ized in Table 2. Resea ch has
highligh ed he c i ical in ol emen o he ansc ip ion ac o ea ly
g ow h esponse 3 (EGR3) in egula ing RELN signaling by binding o i s
p omo e egion (Nie e al., 2021). O e exp ession o EGR3 leads o
neu i e o e g ow h, which can be e e sed h ough RELN dele ion.
No ably, pa ien s wi h SZ exhibi dec eased le els o EGR3 and RELN
mRNA in pe iphe al blood, while pos mo em b ain issue shows o e -
exp ession o bo h ac o s (Nie e al., 2021). Taken oge he , his e i-
dence highligh s a signi ican co ela ion and s ongly sugges s a c i ical
ole o EGR3 in he pa hogenesis o SZ (Nie e al., 2021). Fu he mo e, a
de ici in Reelin exp ession has been shown o impac GABAe gic Pu -
kinje neu on de elopmen du ing ce ebella ma u a ion (Maloku e al.,
2010). Reduced Reelin exp ession was ound in speci ic SZ b ain e-
gions, pa icula ly in he le p e on al co ex, sugges ing a po en ial
ole in neu ological de elopmen and de iciencies in synap ic plas ici y
associa ed wi h he diso de (Habl e al., 2012). Al e a ions in pe iphe al
Reelin exp ession we e also no ed, wi h SZ pa ien s exhibi ing highe
Reelin p o ein concen a ions compa ed o con ols (Ho nig e al.,
2015).
Gene ic s udies ha e also iden i ied posi i e associa ions be ween
Reelin and SZ, p o iding aluable insigh s in o he geno ype-pheno ype
co ela ions associa ed wi h his diso de . A no able 4-RELN-SNP
haplo ype comp ising s362814, s39339, s540058, and s661575 (Bai
e al., 2019), alongside RELN- s362719 (Kuang e al., 2011), demon-
s a ed a s ong associa ion wi h SZ, whe eas ano he haplo ype, TCTC,
appea ed o con e a p o ec i e e ec (Luo e al., 2019). These gene ic
associa ions ha e also been linked o he se e i y and speci ic cha ac-
e is ics o SZ symp oms (Luo e al., 2019). Howe e , some au ho s
sugges ha he en i e RELN gene may no be di ec ly implica ed in SZ
pa hogenesis, as e idenced by he lack o signi ican associa ions wi h
SNPs s155333, s6465938, and s2535764 (Xu e al., 2020). In e es -
ingly, RELN is also belie ed o modula e esponses o an ipsycho ic
ea men , due o he associa ion o he SNPs s362814, s362626, and
s2237628 wi h ea men esponse. This sugges s ha speci ic al e -
a ions in a ious RELN SNPs may se e as p edic i e bioma ke s o
ea men e icacy (Xu e al., 2020). Addi ionally, sex-speci ic associa-
ions be ween RELN SNPs, such as s7341475, and SZ unde sco e di -
e ences in disease de elopmen and pa hogenesis be ween men and
women (Liu e al., 2010; Li e al., 2011; O adia and Shi man, 2011;
Sozuguzel e al., 2019), highligh he complexi y o he con ibu ing
ac o s o he diso de (O adia and Shi man, 2011). O he genes
in ol ed in synap ic plas ici y and neu ological de elopmen linked o
Reelin signaling, including APOE, APOER2, VLDLR, and DAB1, ha e also
been implica ed in memo y pe o mance and cogni i e unc ion in SZ
pa ien s (Ve b ugghe e al., 2012). Finally, gene ic e idence suppo s
RELN as a modi ie gene in SZ pa hogenesis, wi h consis en associa ions
be ween ce ain alleles and symp om se e i y, pa icula ly ega ding
cogni i e impai men and bo h posi i e and nega i e symp oms
(Wedenoja e al., 2010).
F om an epigene ic pe spec i e, Abe g e al. (2014) and Zhou e al.
(2022) showed ha he CpG island me hyla ion a e in he RELN gene
p omo e egion is ele a ed in con ol subjec s compa ed o SZ pa ien s,
wi h no signi ican di e ences iden i ied be ween SZ sub ypes I and II
(Abe g e al., 2014; Zhou e al., 2022). No ably, changes in RELN p o-
mo e me hyla ion induced by cogni i e ehabili a ion he apy we e
associa ed wi h imp o emen s in on o empo al unc ional connec i -
i y in SZ pa ien s, as well as enhanced cogni i e pe o mance, sugges ing
ha epigene ic modi ica ions in RELN may p omo e cogni i e plas ici y
and imp o e ecognized disease ma ke s (Ho e al., 2020). Addi ionally,
highe RELN p omo e me hyla ion in pe iphe al blood was obse ed in
men ela i e o women, indica ing once again a po en ial ole o RELN
me hyla ion in SZ pa hogenesis, pa icula ly among males (Nabil Fik i
e al., 2017). Mo eo e , a signi ican educ ion in global DNA me hyl-
a ion, including he me hyla ion o RELN gene, was obse ed in SZ
subjec s, especially in men, compa ed o heal hy wins, suppo ing he
hypo hesis o an epigene ic model o SZ, whe ein DNA me hyla ion
plays a c ucial ole in gene exp ession egula ion and disease p og es-
sion (B¨
onsch e al., 2012). Las ly, inc eased binding o he enzyme
DNMT1, which ca alyzes he ans e o me hyl g oups o speci ic CpG
si es in DNA, o GABAe gic and glu ama e gic RELN p omo e s was
no ed in SZ pa ien s, al hough his binding did no co ela e wi h
inc eased p omo e me hyla ion (Dong e al., 2015). This DNMT1
binding was p ima ily localized o he co ex and no he ce ebellum,
indica ing a neu on-speci ic mechanism ha is likely independen o
DNA me hyla ion ac i i y (Dong e al., 2015).
4. Discussion
The concep o "demen ia p aecox" in SZ is c ucial o unde s anding
he empo al aspec s o he diso de . Emil K aepelin ca ego ized SZ
wi hin a g oup o clinical synd omes leading o "p ocesses o de e io-
a ion," which he e med "demen ia p aecox" (Ki kpa ick e al., 2008;
Angs , 2002). The au ho di ided endogenous psychoses in o wo main
g oups: manic-dep essi e psychoses, which he conside ed cu able, and
demen ia p aecox, deemed incu able. K aepelin u he e ined his
classi ica ion by dis inguishing be ween wo a ian s o demen ia
p aecox: p og essi e, wi h con inuous de e io a ion, and in e mi en
episodes wi hou i e e sible de ici s (Angs , 2002). This his o ical
pe spec i e aligns wi h he idea o SZ ha ing a neu odegene a i e
componen , simila o AD (Caspi e al., 2024). In his con ex , he Reelin
signaling pa hway, pa icula ly he RELN-APOER2-DAB1 complex, has
eme ged as a c i ical ac o in he neu opa hology o bo h AD and SZ,
o e ing u he insigh in o he neu odegene a i e aspec s o hese
diso de s (An oniades e al., 2011; Ve b ugghe e al., 2012;
B ache -Smi h e al., 2022; Ramsden e al., 2023).
In his sys ema ic e iew, we highligh ha ea ly pTau accumula ion
in AD e lec s disease p og ession (Cuchillo-Ib´
a˜
nez e al., 2016;And a-
de-Gue e o e al., 2023;Zhang e al., 2024) and is linked o dis up ions
in he APOER2-DAB1 signaling pa hway (Cuchillo-Ib´
a˜
nez e al., 2016;
Lid´
on e al., 2020;Ramsden e al., 2023) as well as dec eased Reelin
le els in CSF (No e and Knuesel, 2013;L´
opez-Fon e al., 2019;Lid´
on
e al., 2020;L´
opez-Fon e al., 2022). Neu i ic plaques o ma ion has also
been associa ed wi h hese pa hways (Ramsden e al., 2022, 2023).
Addi ionally, amyloid-be a-induced a ian s o Reelin impai Tau
phospho yla ion, sugges ing ha amyloid-be a may accele a e AD p o-
g ession by dis up ing he RELN pa hway (Ramsden e al., 2022, 2023).
These indings highligh he ole o he RELN-APOER2-DAB1 signaling
pa hway in AD p og ession.
In pa allel, he Reelin signalling pa hway is also in ol ed in he
neu opa hogenesis o SZ h ough a complex ne wo k o molecula in-
e ac ions (Maloku e al., 2010; Habl e al., 2012; Ho nig e al., 2015;
Nie e al., 2021). Al e ed Reelin exp ession, pa icula ly educ ions in
he sho iso o m N-R2 (Fig. 1), has been iden i ied in b ain a eas
associa ed wi h SZ (O adia and Shi man, 2011). As he e showed, gene ic
and biochemical analyses sugges dis up ions in he RELN-DAB1 sig-
nalling pa hway con ibu e o SZ pa hogenesis, wi h a e a ian s o
DAB1 being implica ed (Impagna iello e al., 1998; Guido i e al.,
2000a; Luo e al., 2019; Xu e al., 2020) (Nawa e al., 2020). In e es -
ingly, DAB1 cKO mice exhibi ed beha io al abno mali ies eminiscen o
symp oms obse ed in pa ien s wi h SZ (Imai e al., 2017), suppo ing a
link be ween Reelin le els, synap ic plas ici y, and neu ological de el-
opmen in SZ. Addi ionally, associa ions be ween speci ic RELN SNPs
and SZ ha e been iden i ied (Liu e al., 2010; Kuang e al., 2011; O adia
and Shi man, 2011; Luo e al., 2019; Sozuguzel e al., 2019; Xu e al.,
2020), wi h some a ian s linked o social wi hd awal and impulsi i y
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
8
Table 2
Main indings o s udies on he ole o Reelin signaling pa hway in Schizoph enia.
Zhou e al.
(2022)
Pe iphe al blood. Associa ion be ween
me hyla ion o he CpG
island in he RELN
p omo e egion and
he ypes o posi i e
(Type I) and nega i e
(Type II) SZ.
200 cases e sus
200 con ols.
●Diagnosis o SZ
acco ding o DSM-IV.
●Be ween 18 and 65
yea s old.
●Fi s episode o SZ.
●No ea men 2 weeks
be o e admission.
●Exclusion o
psychia ic
como bidi ies.
●Posi i e and nega i e
symp oms.
●Chinese popula ion.
●Me hyla ion a e o he
CpG island in he RELN
p omo e egion was
highe in he con ol
g oup.
●The e is no di e ence
be ween ype I and ype
II.
●Me hyla ion o he CpG
island in he p omo e
egion o RELN is associa ed
wi h SZ, bu no wi h i s
clinical sub ype.
Nie e al.
(2021)
Pos mo em issue.
Sample o p e on al
co ex (B odmann
A ea 9) and pa ie al
co ex.
Sea ch o new
ansc ip ion ac o s
(TFs) o he Reelin
pa hway in ol ed in
SZ.
●Pos mo em
issue: 5 cases
e sus 5 con ols.
●Pe iphe al
blood: 40 cases
e sus 40 con ols
om a popula ion
in no hwes
China.
●Diagnosis o SZ
acco ding o DSM-IV.
Con ols wi hou
psychia ic his o y. I
includes sex,
como bidi ies, age,
pos mo em in e al and
alcoholism.
●In pe iphe al blood:
pa ien s wi h
medica ion, d ug use,
DM, HTA and umo s a e
excluded.
●EGR3 is a TF ha
egula es Reelin signaling
by binding o i s p omo e
egion.
●O e exp ession o
EGR3 induces neu i e
ou g ow h, e e sible by
dele ion o RELN.
●The amoun o EGR3
and RELN in pe iphe al
blood in SZ subjec s we e
dec eased and co ela ed
wi h each o he .
●EGR3 and RELN a e
o e exp essed in
pos mo em SZ issue.
●EGR3 is a TF o he Reelin
pa hway and egula es
neu i e p oli e a ion.
●EGR3 ia he Reelin
signaling pa hway plays a
ole in he molecula
mechanisms o SZ.
Ho e al.
(2020)
Sali a and pe iphe al
blood samples.
Epigene ic and
beha io al
in ol emen in
molecula changes o
disease e olu ion a e
cogni i e
ehabili a ion (CR).
35 SZ hospi alized
pa ien s e sus 15
heal hy con ols.
Pa ien s admi ed o
cogni i e ehabili a ion
wi h simila p e es IQ
condi ions. Diagnosis o
SZ acco ding o DSM-IV.
Age less han 40 yea s.
Hospi aliza ion o less
han 8 days. No amily
his o y o SZ.
●A e CR, changes in
he p omo e o Reelin
CpG.
●Imp o ed in a on al
and on o empo al
unc ional connec i i y.
●Inc eased cogni i e
pe o mance.
●Changes in Reelin
me hyla ion esul in
inc eased global e icacy and
imp o ed cogni i e
pe o mance.
●CR-d i en epigene ic
modi ica ions on RELN
p omo e cogni i e plas ici y
and imp o e known ma ke s
o disease.
Xu e al.
(2020)
A o al o 15 RELN
SNPs a e geno yped.
E alua ion o he
in luence o RELN on
he esponse o
an ipsycho ic
medica ion.
260 un ela ed
hospi alized
pa ien s wi h SZ.
Gende and age o onse
(18’65 yea s) a e
included. Han Chinese
popula ion. DSM-IV
diagnosis.
The SNPs s udied
s155333, s6465938 and
s2535764 a e no
signi ican .
●RELN a ec s he ou come
o an ipsycho ic ea men .
●RELN SNPs a e p edic i e
bioma ke s o esponse o
an ipsycho ics.
Luo e al.
(2019)
Gene ic analysis. 30
SNPs single nucleo id
polymo phisms o
RELN.
Con ibu ion o RELN
o he p edisposi ion
and se e i y o SZ
symp oms.
102 cases o
un ela ed SZ
pa ien s e sus 169
heal hy con ols.
Samples om he
Thi d People’s
Hospi al in
Zhongsgan,
andomly ec ui ed
om olun ee s.
Sou he n Han Chinese.
Pa ien s wi h posi i e
and nega i e symp oms,
pa anoid o
undi e en ia ed SZ, who
had a is onse o
ecu ence a e s opping
ea men a leas 1
mon h ago. Diagnosis
acco ding o DSM-IV.
Di e ence be ween sex,
age, d ugs, amily
his o y o SZ.
I shows posi i e
associa ions be ween
RELN and SZ. P o ides
in o ma ion on geno ype-
pheno ype co ela ion o
SZ. I sugges s ha RELN
is in ol ed in bo h he
de elopmen and he
se e i y and
cha ac e is ics o SZ
symp oms.
●Haplo ype 4-SNP
consis ing o s362814,
s39339, s540058 and
s661575 highly associa ed
wi h SZ.
●Haplo ype TCTC is a
p o ec i e ac o o SZ.
●Haplo ype 4-SNP is
associa ed wi h social
a oidance, impulsi e and
dange ous beha io in
subjec s wi h SZ.
●Haplo ype composed o
s2229864, s2535764 and
s262355 is ela ed o
hos ili y.
● s727708 is ela ed o
bo h SZ isk and se e i y.
Sozuguzel
e al.
(2019)
Gene ic analysis.
Isola ion o genomic
DNA.
In ol emen o RELN
s7341475 a ian in
SZ.
105 cases o SZ
pa ien s e sus 137
heal hy con ols.
Tu kish popula ion. Age
be ween 18 and 73
yea s. Sex
di e en ia ion.
Diagnosis o SZ
acco ding o DSM-V.
The e was only
associa ion be ween
RELN s7341475 and SZ
in he emale gende .
Samples om Kocaeli
Hospi al.
● s7341475 associa ion
wi h SZ in women.
●No s7341475 associa ion
in he gene al popula ion.
Bai e al.
(2019)
Gene ic s udy. Fou
SNPs ( s1062831,
s3808039, s362746
and s736707) we e
geno yped in he
RELN gene.
Associa ion o RELN
and SZ in samples
classi ied by sex.
1536 pa icipan s. Chinese popula ion.
Di e en ia ion by sex.
● s362746 is associa ed
wi h SZ.
●No sex-speci ic ole is
ound.
●RELN is a gene in ol ed in
he pa hogenesis o SZ.
(con inued on nex page)
A.I. Valde ama-Man illa e al. Neu oscience and Biobeha io al Re iews 169 (2025) 106032
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