Lac o e in as Immune-Enhancemen
S a egy o SARS-CoV-2 In ec ion
in Alzheime ’s Disease Pa ien s
Fe nando Ba olome
´
1,2
, Luigi Rosa
3
, Pie a Valen i
3
, F ancisco Lope a
4
,
Jesu
´s He na
´ndez-Gallego
2,5,6
, Jose
´Luis Can e o
2,7
, Go ka O i e
8,9,10
and E a Ca o
2,11
*
1
G oup o Neu odegene a i e Diseases, Hospi al Uni e si a io 12 de Oc ub e Resea ch Ins i u e (imas12), Mad id, Spain,
2
Ne wo k Cen e o Biomedical Resea ch in Neu odegene a i e Diseases (CIBERNED), Mad id, Spain,
3
Depa men o
Public Heal h and In ec ious Diseases, Uni e si y o Rome “La Sapienza”, Rome, I aly,
4
Neu oscience G oup o An ioquia,
Facul y o Medicine, Uni e si y o An ioquia, Medellı
´n, Colombia,
5
Depa men o Neu ology, Hospi al Uni e si a io 12 de
Oc ub e, Mad id, Spain,
6
Depa men o Medicine, Facul y o Medicine, Complu ense Uni e si y o Mad id, Mad id, Spain,
7
Labo a o y o Func ional Neu oscience, Pablo de Ola ide Uni e si y, Se ille, Spain,
8
Labo a o y o Pha macy and
Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o he Basque Coun y, Vi o ia, Spain,
9
Bioa aba, NanoBioCel
Resea ch G oup, Vi o ia-Gas eiz, Spain,
10
Ne wo ked Cen e o Biomedical Resea ch in Bioenginee ing Bioma e ials and
Nanomedicine (CIBER-BBN), Ba celona, Spain,
11
Neu obiology o Alzheime ’s Disease Uni , Ch onic Disease P og amme,
Ins i u o de Salud Ca los III, Mad id, Spain
Co ona i us 2 (SARS-CoV2) (COVID-19) causes se e e acu e espi a o y synd ome.
Se e e illness o COVID-19 la gely occu s in olde people and ecen e idence indica es
ha demen ed pa ien s ha e highe isk o COVID-19. Addi ionally, COVID-19 u he
enhances he ulne abili y o olde adul s wi h cogni i e damage. A balance be ween he
immune and inflamma o y esponse is necessa y o con ol he in ec ion. Thus,
an imic obial and an i-inflamma o y d ugs a e hope ul he apeu ic agen s o he
ea men o COVID-19. Accumula ing e idence sugges s ha lac o e in (L ) is ac i e
agains SARS-CoV-2, likely due o i s po en an i i al and an i-inflamma o y ac ions ha
ul ima ely imp o es immune sys em esponses. Rema kably, sali a y L le els a e
significan ly educed in di e en Alzheime ’s disease (AD) s ages, which may eflec AD-
ela ed immunological dis u bances, leading o educed de ense mechanisms agains i al
pa hogens and an inc ease o he COVID-19 suscep ibili y. O e all, he e is an u gen
necessi y o p o ec AD pa ien s agains COVID-19, dec easing he isk o i al in ec ions.
In his con ex , we p opose bo ine L (bL ) as a p omising p e en i e he apeu ic ool o
minimize COVID-19 isk in pa ien s wi h demen ia o AD.
Keywo ds: Alzheime ’s disease, demen ia, COVID-19, SARS-CoV2, lac o e in, sali a, b ain-immuni y
in e ac ions, inflamma ion
1 SUMMARY
The co ona i us disease 2019 (COVID-19) pandemic is caused by se e e acu e espi a o y
synd ome co ona i us-2 (SARS-CoV-2) ha a acks mainly he human espi a o y sys em bu
can also access he cen al ne ous sys em (CNS) (1–3). The o al numbe o a ec ed pa ien s
su passes mos o he heal h ca e sys em capaci ies wo ldwide; hence COVID19 pandemic
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782011
Edi ed by:
Samuel Fe na
´ndez Tome
´,
Complu ense Uni e si y o Mad id,
Spain
Re iewed by:
Edoa do Milane i,
Sapienza Uni e si y o Rome, I aly
Huy-Dung Hoang,
Uni e si y o O awa, Canada
*Co espondence:
E a Ca o
[email p o ec ed]
o cid.o g/0000-0002-6504-4579
Special y sec ion:
This a icle was submi ed o
Nu i ional Immunology,
a sec ion o he jou nal
F on ie s in Immunology
Recei ed: 17 Feb ua y 2022
Accep ed: 28 Ma ch 2022
Published: 25 Ap il 2022
Ci a ion:
Ba olome
´F, Rosa L, Valen i P,
Lope a F, He na
´ndez-Gallego J,
Can e o JL, O i e G and Ca o E
(2022) Lac o e in as Immune-
Enhancemen S a egy o
SARS-CoV-2 In ec ion in
Alzheime ’s Disease Pa ien s.
F on . Immunol. 13:878201.
doi: 10.3389/ immu.2022.878201
REVIEW
published: 25 Ap il 2022
doi: 10.3389/ immu.2022.878201
ep esen s an unp eceden ed bu den o coun ies. COVID-19 is
a mul i ac o ious in ec ious disease ha can lead o se e e
mul io gan damage and dea h. Among p e-exis ing medical
como bidi ies, pa ien s wi h demen ia ha e an inc eased isk o
de eloping se e e COVID-19 and mo ali y associa ed wi h i
(4–8). Du ing p e-pandemic imes, pa ien s wi h Alzheime ’s
disease (AD) and o he demen ias a e among he mos
ulne able and dependen pe sons in socie y and his
pandemic has u he exace ba ed hei ulne abili y. These
obse a ions suppo he need o keep sa e pa ien s wi h AD o
demen ia wi hin he al eady discussed s a egic plans o con ol
he COVID-19 pandemic (8,9).
E en i accines can p e en pandemic, nume ous scien ific
in es iga ions a e conside ing an i i al d ug he apy as an
addi ional ea men o COVID-19 pa ien s. Cu en ly, a
numbe o an i i als a e in de elopmen and, some o hem,
such as emdesi i , showed beneficial e ec s educing ime o
eco e y (10). Ano he an i i al d ug candida e, Paxlo id, has
jus ecei ed app o al o FDA Eme gency Use o No el
COVID-19 O al An i i al T ea men in USA, and e y
ecen ly, EMA ecommended i s au ho isa ion in he EU. The
decision came ollowing he esul s ha ea men wi h Paxlo id
significan ly dec eased hospi alisa ions o mo ali y in pa ien s in
isk o su e o se ious COVID-19.
Al hough la ge-scale accina ion is ad ancing a ound he
wo ld, e ec i e an i i als a e absolu ely necessa y. An i i als
ha limi in ec ion and diminish COVID-19 sings would be
ex emely use ul o p o ec ulne able pa ien s helping o s op
his pandemic. Based on his equi emen , epu posing o he US
Food and D ug Adminis a ion (FDA)-app o ed d ugs is a
p omising s a egy o iden i ying apidly deployable
ea men s o COVID-19. In his con ex , lac o e in (L ), a
glycop o ein ound in sec e o y fluids, has been shown o inhibi
SARS-CoV-2 in ec ion, and has been p oposed as a eadily
ansla able he apeu ic op ion o he managemen o
COVID-19 (11–14).
He e, we o e an o e iew ega ding he u gen need o AD
pa ien ’s p o ec ion, ocusing on he inhibi ion o i al in ec ion
h ough he es o a ion o i on homeos asis diso de s as well as
imp o ing immune sys em o figh i al in ec ions, specifically
SARS-CoV-2. We p opose o supplemen he COVID-19 s anda d
ea men wi h bo ine L (bL ), based on i s he apeu ic powe and
scien ific e idence on i s an i i al and an i-inflamma o y ac i i y
(11–15) oge he wi hL deficiency a he sali a y le el in he AD
(16,17).
2 BACKGROUND
2.1 Associa ion Be ween COVID-19
and AD
E idence suppo s he Theo y ha pa ien s wi h demen ia ha e
high COVID-19 isk (8,18). Among CNS como bidi ies o
COVID-19, AD s ands fi s (19), and bo h diseases sha e isk
ac o s, including age, obesi y, ca dio ascula disease,
hype ension and diabe es melli us (20). I has been sugges ed
ha p e-exis ing b ain pa hology and mo e specificmechanis ic
aspec s o demen ia could inc ease he isk o neu ological
complica ions in COVID-19 (21). Blood-b ain ba ie (BBB) in
pa ien s wi h demen ia is damaged, acili a ing he access o
ce ain bac e ia and i uses o he b ain (22,23) husinc easing
he suscep ibili y o in ec ion (24,25). Addi ionally, APOE4,
which con e s inc eased suscep ibili y in de eloping AD, has
been conside ed as a ma ke ha inc eases he se e i y o
COVID-19 (26) he e o e, AD pa ien s who ca y he APOE4
allele ha e a highe isk o de eloping COVID-19.
I has been al eady documen ed ha pa ien s wi h demen ia
a e mo e suscep ible o bac e ial, i al, and ungal in ec ion (24,
25,27–30). These esul s included he p esence o i al and
bac e ial DNA in pos -mo em b ain issues, and/o hei
espec i e an ibodies in he se um o ce eb ospinal fluid
(CSF). Based on all hese s udies, he “In ec ious Hypo hesis”
hasgained ac ionin ecen yea s, which p oposes ha
in ec ious agen s may ha e a causal ole in he de elopmen
o AD. Mo eo e , and based in he close ela ionship be ween
in ec ions and inflamma ion, he In ec ious Hypo hesis
p esumably connec s o he neu oinflamma ion in many ways
(31). Sys emic bac e ial and i al in ec ions may ise he
inflamma o y p ocesses and he p edisposi ion o de elop AD
(32,33). In ec ious ac o s a e esponsible o he ac i a ion o
glial cells ha p oduce se e al inflamma o y molecules,
including cy okines such as umo nec osis ac o (TNF)-a,
in e e on-g(IFN-g), in e leukin (IL)-6, IL-1b,IL-18,
chemokines, and eac i e oxygen species (ROS) which in u n
leads o exace ba ion o o he AD pa hologies. I is impo an o
unde line ha he i on homeos asis diso de s, which lead o an
i on o e load, induce ROS o ma ion (34).
In addi ion, he ch onic inflamma o y p ocesses obse ed in
AD, cha ac e ized by high le els o p o-inflamma o y cy okines,
can ma kedly influence i on homeos asis. In he b ain, i on
modula es di e en unc ions such as high ae obic me abolic
abili y o neu ons, he syn hesis o myelin, he syn hesis and
me abolism o neu o ansmi e s as well as he de elopmen o
he neu onal dend i ic ee (35). In AD pa ien s, magne ic
esonance imaging highligh s an inc ease o i on con en in he
b ains (36). The inc ease o ee i on concen a ion in hese
pa ien s, indica ing a dys egula ion o i on homeos asis,
comp omises b ain unc ions due o he inc ease o oxida i e
s ess associa ed wi h highe ROS and ni ic oxide syn hase (NOS)
p oduc ion (37–39). In he absence o inflamma ion, i on
homeos asis gua an ees a co ec dis ibu ion o his me al
be ween issues/sec e ions and ci cula ion. E e y day 15 mg o
i on a e inges ed om he die bu only 1-2 mg o i on a e daily
abso bed (34).
The e o e, in inflamma o y p ocesses mus be aken in o
accoun ha high le els o hepcidin and low le els o
e opo in (40) cause an i on o e load in cells and sec e ions
oge he wi h i on deficiency in o he blood (41). These pep ides
a e able o modula e i on homeos asis. I is well known ha
pa ien s su e ing om neu ologic diso de s such as AD o o he
kind o demen ia, showed sys emic me abolic diso de s such as
anemia o anemia o inflamma ion (42). Con e sely, low le els o
Ba olome
´e al. Lac o e in and COVID-19 in Demen ia
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782012
hepcidin and high le els o e opo in, es o e i on expo hus
dec easing in acellula i on load and inc easing i on in he
blood (43,44).
O no e, i al in ec ions a e di ec ly p omo ed by in acellula
i on o e load because hei eplica ion is dependen om hos
cell i on enzymes, some o which a e in ol ed in ansc ip ion,
i al mRNA ansla ion, and i al assembly (45). As AD pa ien s
a e cha ac e ized by high concen a ion o in acellula i on (36),
hey ha e an inc eased eplica ion a e o COVID-19 wi h he
consequen neu ological and sys emic complica ions.
SARS-CoV-2 en e s he body mainly as d ople s du ing
inhala ion, and infil a es he nasal and buccal ca i ies o gain
access o he mucosa and he espi a o y ac . Bu SARS-CoV-2
may also en y in o he b ain ac oss he CNS ascula ba ie s
(46). Pa hogens can access o he CNS by se e al ways and
possibly speed up he p og ession o AD. The fi s is h ough a
comp omised BBB. In a heal hy si ua ion, BBB p o ides a
selec i e ba ie o he passage o cells and molecules in o he
b ain; howe e , in a pa hological si ua ion, a comp omised BBB
can allow di ec en y in o he b ain h ough he passage o blood
o he CSF (23,24). Mo eo e , pa hogens, including bac e ia and
i uses can bypass he BBB by en e ing ia he ol ac o y sys em,
because he nasal ca i y connec s he pe iphe al en i onmen o
b ain egions such as he ol ac o y bulb, he en o hinal co ex
and he hippocampus (47). SARS-CoV-2 in ec ion is widesp ead
in epi helial cells, pa icula ly in he lungs, s a ing i s in asion
and en y in o he espi a o y ac . Howe e , as wi h o he i al
in ec ions, SARS-CoV-2 may en e he b ain by i s neu oin asi e
p ope ies, di ec ly by in ec ion o ol ac o y senso y neu ons in
he epi helium and hen anspo ed in o he CNS h ough he
ol ac o y ne e, o c ossing he BBB (46,48).
I is known ha SARS-CoV-2 uses angio ensin-con e ing
enzyme 2 (ACE2) as a ecep o o en e he hos cells and a
ecen a icle epo s ha ACE2 le els a e up egula ed in AD
b ains (49). Al hough some s udies p oposed ha he e was no
clea e idence o human neu onal o as ocy e exp ession o ACE2
(50), mo e ecen findings epo obus ACE2 exp ession in human
neu ons, which is a a ge o SARS-CoV-2 in ec ion (51).
Mo eo e , Ab
42
binds o ACE2 and he spike p o ein S1 subuni
o SARS-CoV-2, enhancing SARS-CoV-2 in ec ion/inflamma ion
(52). Addi ionally, i al in ec ion ecip ocally a ec s Ab
42
clea ance,
ampli ying he p og ession and se e i y o AD. These esul s may
indica e a highe isk o i al en y and loads in he b ain in hese
pa ien s, con ibu ing o unde s and he ela ionships be ween
COVID-19 and he b ain, pa icula ly in AD.
Mos g oups in his field ha e ocused hei esea ch on
ulne abili y o people wi h demen ia o SARS-CoV-2 in ec ion
because hei impai ed memo y impedes hem o comply wi h
he sugges ed public heal h ecommenda ions. Two a en ion-
g abbing pape s discussed his pandemic si ua ion and i s impac
on demen ed pa ien s. In one o hem, Mok and colleagues
discussed he wo ying impac o COVID-19 upon pa ien s wi h
AD and o he demen ias, and p oposed s a egies o ca e and
managemen o hese pa ien s and hei ca egi e s (9). Mo e
ecen ly, a e ospec i e s udy o adul and elde ly pa ien s in he
Uni ed S a es up o 2020 showed ha pa ien s wi h demen ia
we e a highe isk o COVID-19 han hose wi hou demen ia,
and in e es ingly hey ound black people wi h demen ia had
highe isk o COVID-19 han whi e people (8). Resul s o his
s udy highligh he need o keep sa e pa ien s wi h AD o
demen ia, placing special emphasis on he black people, wi hin
he pandemic con ol.
In bo h s udies, au ho s poin ed ou he pa icula
ulne abili y because he mul iplici y o medical condi ions
and social/en i onmen al ac o s. Howe e , in Wang’s s udy,
au ho s specula e ha p eexis ing b ain inju y may allow mo e
i us en y inducing he pa hology o COVID-19 wi hin he
b ain (8), bu , hey also d aw a en ion o a poo immune
esponse/immune dys egula ion as o he s s udies epo ed
(53,54).
Thus, an e ec i e and obus immune esponse may ace
mo e e ec i ely he ou comes o he SARS-CoV-2 in ec ion (55).
I is p oposed ha dys egula ed immune unc ion, including
impai ed an imic obial unc ion, is associa ed wi h inc eased
suscep ibili y o in ec ions (56).
As has been widely seen, pa ien s su e ing o se e e COVID-
19 de elop high le els o p oinflamma o y cy okines and acu e
espi a o y dys unc ion. These inflamma o y p ocesses ha e
been sugges ed o cause cogni i e decline (32,57,58).
Pa hogenically, his si ua ion may esul om di ec nega i e
e ec s o he immune eac ion, exace ba ing o p e-exis ing
cogni i e defici s, o de no o induc ion o neu odegene a i e
disease (Figu e 1).
FIGURE 1 | Schema ic ep esen a ion o po en ial mechanisms o SARS-
CoV-2 in ec ion in neu odegene a ion. SARS-CoV-2 in ec ion causes se e e
up egula ion o p oinflamma o y cy okines and chemokines (so called
“cy okine s o m”) leading o inc eased pe meabili y o BBB and blood-CSF
ba ie , and ini ia ing CNS in asion This e en also in ol es o e ac i a ion o
glial cells ha can p omo e de imen al e ec s, indi ec ly and/o di ec ly, by
inducing synapse loss, oxida i e inju y and u he con ibu ing o neu onal
degene a ion.
Ba olome
´e al. Lac o e in and COVID-19 in Demen ia
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782013
Unde s anding he ela ionship be ween immune
dys egula ion, in ec ions and demen ia has aken on new
u gency in he COVID-19 pandemic.
2.2 Impac o he Immune Sys em in AD
The bidi ec ional pa hways be ween he CNS and pe iphe al
immuni y a e called he neu oimmune axis, and e en i a e a
om being comple ely unde s ood (59–62). Neu ological
inflamma ion diso de s a e hough o be caused by
dys egula ed a e en ne e neu oimmune pa hways (62,63).
Rega ding he possible oles ha may play in he pa hology o
AD he dysbiosis o in ec ions ou side he CNS, he e a e limi ed
da a. Howe e , gi en he ole o inna e immuni y in AD has
become clea in ecen yea s, as well as he connec ion be ween
he neu oimmune axis and neu oinflamma ion, we belie e ha
mo e a en ion should be paid o he con ibu ions o ch onic
pe iphe al in ec ion on ce eb al AD pa hology.
As we ecen ly discussed, he e olu ion o AD pa hology is
associa ed wi h immuni y dys un ion (56). Al e a ions in he
immune esponses may occu a ea ly s ages o AD and possibly
a e in ol ed in he AD p og ession, as epo ed in p e ious
expe imen al and clinical s udies (64). Th oughou aging, he e is
a loss o ana omical and physiological in eg i y, which causes a
g ea e ulne abili y o some diseases and dea h. Aging is
induced by gene ic, epigene ic and en i onmen al ac o s and
a ec s almos all o gans, ha ing a p o ound impac on he
immune sys em (65,66). Mo eo e , se e al s udies pos ula ed
ha AD pa hology is unde he con ol o he immune sys em in
an age-dependen manne (67–69). Now, AD is conside a
sys emic disease wi h a s ong cen al and pe iphe al
neu oinflamma o y componen . Immune cells may a el o
and om he b ain due o he inc eased pe meabili y o he
BBB in AD, pa icipa ing in he pa hogenesis and p og ession o
his neu odegene a i e diso de (69). G owing e idence sugges s
ha pe iphe al in ec ions may igge he build-up o amyloid
plaques in he b ain by modula ing glial cells, elici ing an
immune eac ion and s imula ing sec e ase ac i i y ha
inc ease he p oduc ion o amyloid pep ides (70,71). O e he
las decade, he p esence o a sus ained immune esponse in he
b ain has been p oposed as a key elemen in AD pa hology.
Neu oinflamma ion, including he ac i a ion o glial cells and
o he immune cells, has been demons a ed o agg a a e AD–
ela ed pa hology (72). Acu e inflamma o y esponses a e
common o heal hy indi iduals, howe e ch onic inflamma ion
impai s he na u al balance o p o- and an i-inflamma o y
signaling in he b ain, p esumably leading o he de elopmen
and p og ession o neu odegene a i e diseases such as AD (72).
The inna e immune sys em induces an essen ial con ol o e
sali a y sec e ion in he o al ca i y. The nasal ca i y is he majo
po al o en y o pa hogens as well as he o al ca i y which
homeos asis is main ained by sali a. The mos ele an sali a y
agen s esponsible o he de ense agains mic obial pa hogens
a e an imic obial pep ides and p o eins (AMPs), which a e he
p ima y inna e immune e ec o s and cons i u e he fi s line o
de ense agains pa hogen in ade s (73,74).
In humans, AMPs a e p oduced by many cells, including
phagocy es, epi helial and endo helial cells (75). Pa icula ly,
AMPs a e highly exp essed in he b ain and o he
immunop i ileged o gans whe e he ac i i ies o adap i e
immuni y a e cons ained, and low AMP le els can esul in
se iously comp omised immuni y. AMP exp ession can be
induced du ing inflamma ion o a e mic obial in ec ions. I has
p oposed ha dys egula ion o AMP ac i i ies may be in ol ed in
hepa hologyo ch onicinflamma o y diseases and
neu odegene a i e diso de s (76). The no mal p oduc ion o
AMPs may be educed as a esul o ac o s such as a debili a ed
immune sys em, damaged de ense cells (by ei he in acellula
in ec ions o apop o ic p ocesses), o s uc u al i amin D
deficiency (77). Down- egula ion o AMPs is associa ed wi h
ch onic inflamma o y diseases, including C ohn’sdisease(78).
As p e iously discussed, he inna e immune sys em u ilizes
AMPs as he p ima y e ec o p o eins o a ack in ading
mic oo ganisms, such as bac e ia, i uses o ungi (79). By
binding hos biomolecules linked o immuni y, AMPs a e also
po en immunomodula o s ha play an impo an ole in
comba ing in ec ion. AMPs modula e bo h inna e and adap i e
immune sys ems which no mally wo k as a con inuum (80). In
ac , AMPs a e some imes known as ala mins due o hei ole in
s imula ing adap i e immune pa hways, including he
complemen sys em.
2.2.1 Sali a y AMPs in AD
Recen disco e ies on inflamma ion-media ed neu odegene a ion
and he ole o Abin immuni y ha e led o he eme ging o he
“An imic obial P o ec ion Hypo hesis”in AD (81). AMPs ha e
been p oposed as a po en ial al e na i e o he de ec ion and
diagnos ic ollow-up o such ce eb al in ec ions ha a ec he Ab
accumula ion in he b ain (82). Fu he mo e, an imic obial
he apies could also be e ec i e in a acking AD pa hology (83).
The hos - esponse consis s o a cascade o e en s by he
inna e and acqui ed immuni y. An ea ly componen o he hos
esponse is he sec e ion o AMPs by sali a y glands, o al
epi helial cells and neu ophils. Sali a p o ides aluable
in o ma ion on o al and sys emic heal h. Mos o he sali a y
compounds a e locally p oduced in he sali a y glands, bu some
o he s can come om blood, such as sec e o y IgA, anspo ed
by ac i e anspo , ions, ca echolamines, and s e oids,
anspo ed by ul afil a ion mechanism, o plasma albumin
which en e sali a by ansuda ion in o he o al ca i y (84). Sali a
significan ly con ibu es o he p o ec i e ba ie o o al
epi helium h ough i s con en o AMPs, which may ha e an
impo an ole in inna e hos de ense. Sali a con ains a la ge
panel o an imic obial p o eins including L , lac ope oxidase,
lysozyme and an imic obial pep ides ha bo h di ec ly o
indi ec ly inhibi he uncon olled ou g ow h o pa hogens.
Al hough he concen a ions o some o hese molecules a e
qui e low, hei e ec s a e addi i e and/o syne gis ic,
cons i u ing an e ficien molecula de ense sys em o he o al
ca i y (85).
Sali a y p o eins, including AMPs, a e eleased om sali a y
glands unde he au onomic ne ous sys em con ol h ough he
elease and ac i a ion o ace ylcholine (ACh) om
pa asympa he ic ne es (86–89). The p ima y pa asympa he ic
sali a y cen e s connec wi h he la e al hypo halamus.
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´e al. Lac o e in and COVID-19 in Demen ia
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782014
De elopmen o immune diso de s may o igina e sali a y gland
dys unc ion. We sugges ed oge he wi h o he au ho s ha AD-
ela ed immune sys em dis u bances migh be a esul o
neu ological al e a ions de e mined by hypo halamic lesions
(56,60,90). Rein o cing his hypo hesis, we ha e ecen ly
epo ed educed ACh elease measu ed in submandibula
glands om APP/PS1 double- ansgenic mice model o AD
(91). Addi ionally, we ound lowe sali a y L le els in his
mouse compa ed wi h non- ansgenic mice, sugges ing a
specific dys unc ion in he AD sali a y glands associa ed wi h
an al e ed ACh signaling pa hway. These findings a e consis en
wi h hose p e iously epo ed in AD pa ien s showing lowe
sali a y L le els in p od omal and clinical AD (16,17).
2.2.2 Role o Sali a y L in AD
L , an 80 kDa i on-chela ing ca ionic glycop o ein belonging o he
ans e in amily, exe s se e al unc ions, such as an ibac e ial,
an i ungal, an i i al, an ipa asi ic, an i-inflamma o y and
immunomodula o y ac i i ies (34,92–95). Human L (hL ) is
exp essed in a a ie y o issues and fluids including b eas milk,
colos um, sali a, ea s, mucous, as well as i is p esen in he
seconda y g anules o neu ophils (96–98). HL is one o he majo
p o eins in all exoc ine sec e ions, including sali a, which is
associa ed wi h hos de ense agains o al pa hogens. The
concen a ion o sali a y hL in heal hy subjec s anges be ween
3.9 and 14.5 µg/ml (99)wi hmean alueso 8.96and7.11µg/mlin
uns imula ed and s imula ed sali a, espec i ely as has been
epo ed by au ho s (100). Sali a y hL concen a ion is also
influenced by gende (34), age (101,102), and he physiological
o pa hological s a us o he subjec (99,103–105). Conce ning he
pa hological s a us o he subjec s, a c oss-sec ional s udy showed
ha sali a y hL le els a e dec eased in pa ien s su e ing om mild
cogni i e impai men (MCI) and AD compa ed wi h age-ma ched
heal hy subjec s (16), indica ing a pu a i e link be ween AD, he
immune sys em, and b ain in ec ions. In addi ion, sali a y hL has
been p oposed o be use ul o de ec MCI o p od omal AD and o
disc imina e AD om o he ype o demen ias, as sali a y hL le els
a e associa ed wi h he amyloid-PET imaging p ofile (17).
Mo eo e , i has been jus epo ed ha sali a y hL is nega i ely
associa ed wi h egional Abload and wo se memo y (106). Based
on all hese esul s, we suppo he ole o sali a y hL as a
bioma ke o ce eb al ulne abili y in physiological aging. In
addi ion, we sugges ed ha sali a y le els o hL could be educed
as a consequence o he immunological diso de s associa ed wi h
AD. Mo eo e , changes in sys emic immuni y du ing AD
p og ession could be a downs eam e ec o ea ly AD
pa hology (56).
Sali a y hL is in ol ed in he egula ing o he o al mic obio a
and he inflamma o y s a e o he o al mucosa, con ibu ing o he
p ese a ion o symbiosis in he hos -mic obiome ela ionship
(107). The e o e, when sali a y hL le els dec eased, as seen in
AD pa ien s, i would be expec ed ha he e would be an ad ance o
o al dysbiosis. E en in aged subjec s wi h o al d yness, sali a y le els
o hL we e educed and his may aid he access o o al pa hogens o
he b ain (101). In addi ion, Olsen and Singh ao p oposed ha
sali a y hL defici may ac as an ac i a o o o al mic obial
dysbiosis, suppo ing he concep ha low le els o hL migh
indica e o al dysbiosis (108).
O he s udies ha e also suppo ed ha o al pa hogens could
deg ade hL (109,110). This could acili a e he p oli e a ion o
some o hese pa hogens, augmen ing o al in ec ions, and
p obably p omo ing AD by sys emic dissemina ion o hese
pa hogens and he inflamma o y signaling in he b ain. In an
elde ly pe son wi h de e io a ed BBB, o al mic oo ganisms and
inflamma o y media o s can each he b ain h ough he blood
s eam. The e o e, as Olsen and Singh ao p oposed, i is highly
plausible ha low sali a y hL le els could p omo e he
p opaga ion o o al- ela ed mic oo ganisms and inflamma o y
molecules o he b ain by educing inna e immuni y (108).
Low sali a y le els o hL in AD pa ien s may a ec i s b ain
concen a ion since sali a y hL may be anspo ed in o he
b ain ia he sublingual ou e (111). As ma e o ac , L can
easily c oss he BBB because L ecep o s (L R) a e p esen on
he memb ane o BBB endo helial cells (112), hus exe ing i s
mul iple unc ions. In e es ingly, unde pa hological
condi ions, such as AD, an inc ease o L R exp ession on
mic o essels and neu ons has been epo ed (113). As
consequence, a apid L up ake by L R and high a ailabili y
in he b ain ha e been obse ed (112).
2.2.3 I on Chela ion Agen s o L in AD T ea men
In he las yea s, as i on bu den exe s an impo an ole in he
AD pa hology, i on-chela ing compounds go a lo o a en ion.
Howe e , he en y o d ugs in o he b ain is es ic ed by he
BBB. The e o e, an i on-chela ing agen , ideal o ea ing AD,
mus easily pass h ough he BBB. Fo his pu pose,
nano echnological app oaches ha e been s udied (114) oge he
wi h me hods o in anasal adminis a ion (115). Among i on-
chela ing compounds, de e oxamine (DFO) showed beneficial
e ec s in expe imen al s udies, as shown a e in amuscula , o al
o in anasal adminis a ion in AD pa ien s (116–118). Howe e ,
DFO shows a poo bioa ailabili y and induces some side e ec s
such as neu o oxici y in p olonged ea men s as well as
gas oin es inal malabso p ion (39,117–119).
Di e en ly om i on-chela ing compounds, L adminis a ion
seems o be ac i e agains anemia o anemia o inflamma ion as well
as agains AD (120). L has been ound o e e i on homeos asis
illnesses induced by inflamma o y p ocesses by down- egula ing IL-
6 and hepcidin and up- egula ing e opo in exp ession,
ees ablishing i on expo om cells in o blood (41,121–124).
Mo eo e , L in mac ophages is also able o up- egula e T R1,
and down- egula e cy osolic e i in (125,126).
The e o e, L h ough i s po en an i-inflamma o y ac i i y
and i s e ficacy in modula ing i on p o ein as e opo in, T R1,
e i in and hepcidin is eme ging as a na u al subs ance ha can
be applied in he p e en ion and cu e o anemia wi hou side
e ec s (124). In e es ingly, Guo and colleagues (2017) epo ed
ha in anasal ecombinan hL ( hL ) ea men educes Ab
agg ega ion and cogni i e impai men in an AD mouse model.
Fu he mo e, his hL ea men p o ec s he b ain om
oxida i e s ess, showing dec ease significan educ ion o ROS,
TNF-aand IL-6 le els in he b ain (127).
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´e al. Lac o e in and COVID-19 in Demen ia
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782015
In ano he clinical ial, he bL ea men leads o a dec ease o
IL-6 and an inc ease IL-10 in se um (128). L has been p oposed o
be beneficial in AD pa ien s, since his mul i unc ional p o ein
may alle ia e he AD pa hological cascade by educing Ab-
agg ega ion, auopa hy, sp ead inflamma ion and oxida i e
s ess, and neu onal damage (120,128,129). Based on all hese
s udies, bL supplemen s a e cu en ly conside ed as a plausible
he apy o AD.
2.3 BL in COVID-19 T ea men
Since he immune s a us plays a c ucial ole in disease se e i y,
immuno he apies a e used in se e ely ill COVID-19 pa ien s
(130). Based on he an i-inflamma o y, an i- i al and immune-
egula ing p ope ies o bL (95), which a e in acco dance wi h
he ea men supplies o SARS-CoV-2 in ec ion, bL migh be
use ul in he p e en ion and/o managemen o COVID-19.
Indeed, bL could exe mul iple unc ions, including a
p ima y de ense ac o agains mucosal in ec ions, and a
modula o o i al in ec ious p ocesses. I s an i i al ac i i y is
media ed by he L binding o hepa an sulpha e
glycosaminoglycans (HSPGs) o hos cells, i al pa icles o
bo h (93).
Recen ly, many in i o s udies shown ha bL is ac i e
agains SARS-CoV-2 (11,12,131,132). In hese s udies, bL
shows an i i al ac i i y agains SARS-CoV-2 wi h a mul imodal
mechanism: (i) h ough i s binding wi h HPSGs o hos cells,
which blocks he anspo o i al pa icles o he high-a fini y
specific en y as ACE-2 (131); (ii) h ough i s binding o spike
glycop o eins o SARS-CoV-2, hus hinde ing he i al adhesion
o hos cells su ace (12); and (iii) h ough he up egula ion o
in e e on I sys em hus ac i a ing he hos an i i al esponse
(11,132). All hese findings p opose he beneficial bL e ec s in
hos de ense agains SARS-CoV-2.
As epo ed in he p es igious Lance jou nal, mo ali y om
COVID-19 is no simply due o i al in ec ion bu is a esul o a
cy okine s o m synd ome associa ed wi h hype inflamma ion
leading o acu e espi a o y dis ess and subsequen mo ali y
(133). By he way, many s udies shown ha bL was able o
modula e his cy okine p ofile in COVID-19 cases by educing
educe IL-6 and TNFale els (126,134–138). Mo eo e , bL may
diminish inflamma o y ac o elease by p omo ing di e en
ac ions (139). I was epo ed ha a e o al adminis a ion o
bL , he killing ac i i y o NK cells was highe agains i us-
in ec ed cells, enhancing he p oduc ion o IL-18 (140). Also, bL
may ise IL-12 le els in mac ophagocy es, p omo ing he
mig a ion o mac ophages o inflamma o y si es (141).
As Zimecki and colleagues summa ize in hei ecen e iew,
se e al s udies s ongly sugges he u ili y o bL o silence he
“cy okine s o m”, suppo ing i s po en ial o he handling o
SARS-CoV-2 in ec ion (142).
Based on p eclinical s udies, Rosa and colleagues de eloped a
ecen s udy o assess he e ficacy o o al bL on ambula o y
COVID-19 pa ien s (13). Resul s o his s udy e ealed ha he
ime equi ed achie ing SARS-CoV-2 RNA nega i iza ion in
bL - ea ed pa ien s was lowe compa ed o ha epo ed in bL
un ea ed pa ien s (15 e sus 24 days). This means ha he bL
ea men may imp o e ou comes in pa ien s su e ing om
COVID-19, including hose wi h como bid diseases, and
ad anced age. Fu he mo e, hey de ec ed a e y in e es ing
associa ion be ween symp om educ ion and age: bL was able
o educe he ime o symp om esolu ion wi h ad ancing age
(13). This ac could be associa ed wi h he ho monal con ol o
hL syn hesis (143), and ha dec eases wi h age. The la e is
pa icula ly ele an o AD pa ien s showing lowe sali a y hL
le els (16,17).
In ano he clinical s udy in To Ve ga a Uni e si y Hospi al
(Rome, I aly), o al and in anasal liposomal bL was
adminis e ed in asymp oma ic and mild- o-mode a e COVID-
19 pa ien s compa ed o s anda d o ca e (SOC)- ea ed and
un ea ed COVID-19 pa ien s (14). In ag eemen wi h p e iously
epo ed da a (13), significan ly less mean ime o SARS-CoV-2
RNA nega i e con e sion was de ec ed in a liposomal bL -
ea ed g oup compa ed o SOC- ea ed and un ea ed pa ien s
(14 e sus 27 days), wi h as clinical symp oms eco e y (14).
Mo eo e , in liposomal bL - ea ed pa ien s, a significan
educ ion in se um IL-6, e i in and D-dime s le els was
shown (14).
O e all, e en i he andomized clinical ials on a la ge
numbe o COVID-19 pa ien s a e equi ed, hese clinical
expe iences indica e ha ea ly ea men o bL on COVID-19
pa ien s could be he winning s a egy o a oid he disease
p og ession and se e i y, especially in he pa ien s su e ing
om como bid diseases and ad anced age.
3 CHALLENGE IN AD PATIENT
PROTECTION AGAINST COVID-19
Al hough we ha e gained a g ea e unde s anding o he impac
o COVID‐19 on demen ia, and pa icula ly on AD, u he
esea ch is u gen ly needed o p o ec hese ulne able pa ien s
agains COVID-19, con olling he isk o i al in ec ions.
Implemen ing p e en ion o in ec ion and su eillance
measu es is i ally impo an . S udies aimed a educe he
ad e se esponse o COVID-19 in ec ion in AD pa ien s o
wi h a dual app oach including bo h, ea ly de ec ion p og ams,
whe e he p ima y heal h sys em will be implica ed, and
he apeu ic in e en ions will be help ul and necessa y.
Al hougha he imeo w i ing he ea eanumbe o
an i i als in de elopmen as po en ial ea men s o COVID-
19, and a ew o hem a e al eady app o ed, we p opose ha an
addi ional app oach ocused on p e en ing he isk o in ec ion
would be e y use ul. Ou s a egy would be ocused on hose
ulne able popula ions o COVID-19 in ec ion, specifically AD
pa ien s, wi h impai ed inna e‐immune de enses. They would be
easily de ec ed by using a e y simple and non-in asi e es (i.e.,
measu ing sali a y L le els).
He e, we p opose a double s a egy aimed a educing he
ulne abili y o AD pa ien s agains SARS-CoV-2in ec ion by
enhancing immune sys em: he fi s app oach would be o
measu e sali a y hL le els and he second would be o es o e
an imic obial de ense including bL supplemen a ion, which
would educe SARS-CoV-2 ac ions based on he mul i unc ional
Ba olome
´e al. Lac o e in and COVID-19 in Demen ia
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782016
p ope ies o bL (i.e., an i i al and an i-inflamma o y ac i i ies).
As discussed by Be mejo and colleagues, AD pa hology is closely
ela ed o he immune sys em ha may be eflec ed as an impai ed
inna e‐immune esponse (i.e., educed AMPs p oduc ion,
including sali a y L ) (56). Sali a y L p oduc ion is influenced
by age. We and o he s e ealed educed L ac i i y and le els in
heal hy elde ly subjec s, being significan in he ou h decade
(144–146). In e es ingly, his educ ion is exace ba ed no only in
AD-diagnosed pa ien s (16,17), bu also in memo y impai ed
subjec s associa ed wi h b ain Abbu den (106). Al hough mo e
unc ional s udies o analyze in he CNS he consequences o
al e ed sali a y L le els in AD would be necessa y, i is close clea
ha educed sali a y L le els may be used o iden i y demen ed
and cogni i e impai ed people due o AD suscep ible o in ec ion
by SARS-CoV-2 (Figu e 2). Ou s a egy could be especially use ul
in less de eloped coun ies whe e COVID-19 bu also AD
incidence a e g owing and ha e de as a ing consequences o
hei popula ion.
The need o implemen s anda ds and p o ocols aimed a
p e en ing o SARS-CoV-2 in ec ion is c ucial o a oid o a less
educe g ea e isk o COVID-19 mo bidi y and mo ali y. In
his ega d, we p opose o in oduce con ol s a egies in he
p ima y ca e heal h sys em ocused on moni o ing he immune
s a us o AD pa ien s and o he ulne able people wi h o
wi hou demen ia (i.e., subjec s wi h subjec i e memo y loss).
Because o he p essu e on he sani a y sys em caused by he
COVID-19 pandemic, analy ical me hods o e alua e he
immune s a us should be as , ela i ely cheap, and should no
equi e specialized pe sonnel. In he fluid bioma ke field,
sali a y bioma ke s p o ide a apid and e ficien disease
diagnosis. Wi h he e idence ha L ep esen s an impo an
de ensi e elemen as a modula o o he immune esponse, we
p opose ha sali a y L could be a use ul ool o he sc eening o
hese ulne able olde people. Addi ionally, u he s udies a e
needed conce ning molecula and unc ional links be ween
sali a y immune bioma ke s and AD neu odegene a ion
add essing ques ions like, when do hese immune al e a ions
appea ?; do hey appea be o e o a e he fi s clinical
symp oms o demen ia?; how long do hey emain?
Mo eo e , cumula i e e idence suppo he an i- i al
ac i i y o bL which in e ac s wi h cell HSPGs and SARS-
CoV-2 spike glycop o eins, hus appea ing a hope ul al e na i e
o he ea men o COVID−19 (Figu e 2). As widely
suppo ed by Zimecki and colleagues, bL may be o clinical
benefi s in he dec easing o he SARS-CoV-2- induced
cy okine s o m (142). We sugges ha sali a y L dec ease
may be a esul o impai ed inna e‐immune de enses, and
consequen ly he elde ly would be mo e suscep ible o
in ec ions. The clinical expe iences epo ed by Rosa e al.
(13)andCampionee al.(14) indica e ha ea ly ea men o
bL on COVID-19 pa ien s could be he winning s a egy o
a oid he disease p og ession and se e i y, especially in he
pa ien s su e ing om como bidi ies and ad anced age.
AD pa ien s who a e mo e p one o COVID-19- ela ed
dea hs due o immune dys egula ion and i on homeos asis
diso de s a e likely o benefi om L supplemen s.
Ne e heless, we ecommend u he clinical s udies o alida e
L in AD pa ien s agains COVID-19 in ec ion o p o e i s
e ficacy in o e coming a hype -inflamma ion s a us and
cogni i e impai men s, hus educing mo ali y. In addi ion, i
is possible ha L supplemen s can also be supplied as a
p e en i e ea men o hose ulne able olde people as a
pha macological s a egy o ein o ce hei immune esponse.
Howe e , mo e knowledge is needed o de e mine i his s a egy
is uly p o ec i e and which a e he e en s and molecula
pa hways in ol ed.
FIGURE 2 | Po en ial ole o L in he ela ionship be ween AD b ain pa hology and COVID-19. Pa hogenic e en s leading o neu onal damage may impai he hos
de ense sys em which in u n educe AMP p oduc ion, including L , and influence he ex en o SARS-CoV-2 in ec ion in he b ain. Addi ionally, po en ial an i i al
mechanisms o L a e shown: (1) by modula ing SARS-CoV-2 induced inflama ion, educing p o-inflamma o y cy okine le els, such as IL-6 and TNFa; (2) by occupying
binding si es o SARS-CoV-2, as hepa an sul a e p o eoglycans (HSPGs) on he hos cell su ace, educing i al su fing and subsequen i al en y; and
(3) by inhibi ion o i al eplica ion ia induc ion o in acellula cell signals. AD, Alzheime ’s disease; L , lac o e in; AMP, an imic obial pep ide; BBB, blood-b ain ba ie .
Ba olome
´e al. Lac o e in and COVID-19 in Demen ia
F on ie s in Immunology | www. on ie sin.o g Ap il 2022 | Volume 13 | A icle 8782017
4 CONCLUSIONS
He e we examine e idences o he ela ionship be ween SARS-
CoV-2 in ec ion and AD suppo ing ha people wi h his
neu odegene a i e disease ha e an inc eased isk o i al
in ec ion, p obably dependen om an i on o e load, an
inflamma o y p ocess and a deficien immune esponse. As an
an i i al agen , L wo ks di ec ly o indi ec ly on he i al
pa icles and is being used o se e al heal h pu poses. A his
ime, mo e han 170 clinical ials include bL . Since bL
ep esen s an easily a ailable and sa e na u al glycop o ein, i
may become a new p e en i e app oach o help he ulne able
popula ion, including AD pa ien s su e ing om COVID-19.
Howe e , ques ions s ill emain as o whe he bL he apeu ic
in e en ion could a oid SARS-CoV-2 in ec ion. Fu u e s udies
should conside e alua ing hese aspec s h ough p eclinical and
subsequen clinical ials. We p opose es ing he le els o
sali a y L in he popula ion a isk (AD pa ien s and/o
heal hy olde subjec s wi h subjec i e memo y loss) and
planning in e en ions o aise i s le els. I is impo an o
unde line ha di e en bL o mula ions a e comme cialized:
o osoluble able s, in anasal sp ay and o al capsules could be he
winning s a egy o inc ease sali a y L le els and o p o ec AD
pa ien s om SARS-CoV-2 in ec ion. The use o o osoluble
able s and he in anasal sp ay is ac i e agains SARS-CoV-2
h ough bL binding wi h cell HSPGs and i al spike
glycop o eins, wi h hinde s i al in ec ion. These s a egies
should inco po a e andomized, placebo-con olled, pa allel-
g oup Phase-1 clinical ials o de e mine in hese pa icipan s
he p elimina y e ficacy and impac o bL on COVID-19. Well-
designed clinical s udies a e needed o u he alida e he use o
bL as e ec i e ea men in he SARS-CoV-2 in ec ion.
Al hough COVID-19 accina ion is wo king success ully, in
he cu en scena io we s ongly belie e nu aceu ical
supplemen s, including L , appea o be p omising al e na i e
solu ions o he p e en ion and ea men o COVID-19.
AUTHOR CONTRIBUTIONS
EC: concep ion and design o he s udy, d a ing he manusc ip
and figu es. FB: d a ing he manusc ip . LR and PV: d a ing
and c i ical e iew o he manusc ip . FL: d a ing and c i ical
e iew o he manusc ip . JC: d a ing and c i ical e iew o he
manusc ip . JH-G: d a ing he manusc ip . GO: d a ing and
c i ical e iew o he manusc ip . All au ho s ha e ead and
ag eed o he published e sion o he manusc ip .
FUNDING
This s udy was suppo ed by g an s om Ins i u o de Salud
Ca los III (FIS21/00679 o EC and JH-G and PI21/00183 o FB),
FEDER, Comunidad de Mad id (S2017/BMD-3700;
NEUROMETAB-CM o EC), and CIBERNED (CB07/502 o
EC); Spanish Minis y o Economy and Compe i i eness
(PID2020-119978RB-I00 o JC), CIBERNED, he Resea ch
P og am o a Long-Li e Socie y (0551_PSL_6_E o JC), he
Jun a de Andalucıa (PY20_00858 o J.L.C.), he Andalucıa-
FEDER P og am (UPO-1380913 o JC).
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