THE

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Modulation of innate immunity of patients withAlzheimer’s disease by omega-3 fatty acidsMilan Fiala,*,1 Gijs Kooij,†,‡ Karen Wagner,§ Bruce Hammock,§ and Matteo Pellegrini**Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA; †Departmentof Molecular Cell Biology and Immunology, Vrije Universiteit (VU) Medical Center, Multiple Sclerosis Center Amsterdam, Amsterdam, TheNetherlands; ‡Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology,Harvard Institutes of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; and §Departmentof Entomology, University of California, Davis, Davis, California, USA

ABSTRACT:The innate immune systemof patientswithAlzheimer’s disease andmild cognitive impairment (MCI) isderegulated with highly increased or decreased transcription of inflammatory genes and consistently depressedphagocytosis of amyloid-b1-42 (Ab) by monocytes and macrophages. Current immune therapies target singlemechanisms in the adaptive immune system but not innate immunity. Here, we summarize recent advances intherapy by v-3, v-6, and epoxy fatty acids; specialized proresolving mediators; and vitamin D3 that have provenimmune effects and emerging cognitive effects in patients with MCI. The hypothesis of this approach is thatmacrophages of normal participants, but not those of patientswith Alzheimer’s disease andMCI, possess effectivephagocytosis forAb andprotecthomeostasisof thebrainand, furthermore, thatdefectiveMCImacrophages recoverphagocytic function viav-3. Recent studies of fish-derivedv-3 supplementation in patientswithMCI have shownpolarization of Apo«3/«3 patients’ macrophages to an intermediate M1-M2 phenotype that is optimal for Abphagocytosis and the stabilizationof cognitivedecline.Therefore, accumulatingpreclinical andpreliminary clinicalevidence indicates thatv-3 supplementation should be tested in a randomized controlled clinical trial and that theanalysis should involve the apolipoprotein E genotype and intervening conditions during trial.—Fiala, M., Kooij,G.,Wagner,K.,Hammock,B.,Pellegrini,M.Modulationof innate immunityofpatientswithAlzheimer’sdiseasebyomega-3 fatty acids. FASEB J. 31, 000–000 (2017). www.fasebj.org

Alzheimer’s disease (AD) is a neurodegenerative diseasethat is preceded by prodromal stages of mild cognitiveimpairment (MCI) (1) and subjective cognitive impair-ment (2) that frequently are not recognized but are im-portant for the start of preventive therapy. To date, there isno proven effective therapy to counteract the progressionof MCI to AD, which has a 42.5% incidence at 5 yr (3);however, it is accepted that any therapy should addressinflammatory damage and clearance of amyloid-b1-42(Ab) (4). Potential therapeutics include v-3 fatty acid–derived proresolving mediators, which induce anti-

inflammatory and proresolving responses and enhancemacrophage phagocytosis (5), including the phagocytosisof Ab (6). In addition, the v-6 fatty acid arachidonicacid–derived mediator, epoxyeicosatrienoic acid (EET),displays potent anti-inflammatory and antinociceptiveproperties (7). Recent discoveries that have bearing on thetranscriptional deregulation of innate immunity againstAb (6) and alterations in resolution pathways in the CNSof patients with AD (8) suggest that v-3 lipid mediatorsshould be tested in a controlled trial.

MACROPHAGES AND MICROGLIA IN THE ADBRAIN: HARMFUL INFLAMMATION ANDBENEFICIAL CLEARANCE OF Ab

Roles in AD of microglia- vs. monocyte-derived macro-phages have been discussed since the 90s. Microglia thatoriginate from bone marrow were shown to clear Ab (9)but also tohave toxic effects onneurons (10). Inflammationin the AD brain was attributed to Ab deposits that hadbeen invaded by microglia and surrounded by reactiveastrocytes (11). Monocytes were attracted into neuropilacross the human blood-brain barrier (BBB) model byCCL2, -3, and -4 chemokines (12) and, inmousemodels, by

ABBREVIATIONS: 1,25D3, 1a,25-dihydroxy vitamin D3; Ab, amyloid-b1-42;AD, Alzheimer’s disease; APOE, apolipoprotein E; AT, aspirin-triggered;BBB, blood-brain barrier; DHA, docosahexaenoic acid; EET, epoxy-eicosatrienoic acid; EPA, eicosapentaenoic acid; EpFA, epoxy fatty acid;GlcNAc, b-1,4-mannosyl-glycoprotein4-b-N-acetylglucosaminyltransfer-ase; IRF, IFN regulatory factor; LXA4, lipoxin A4; MaR1, maresin 1; MCI,mild cognitive impairment; MMSE, minimental state examination; PPAR,peroxisome proliferator-activated receptor; PUFA, polyunsaturated fattyacid; RvD, resolvin D; RXR, retinoid X receptor; sHE, soluble epoxidehydrolase; SPM, specialized proresolving mediator; STAT, signal trans-ducer and activator of transcription1 Correspondence: UCLA School of Medicine, 100 UCLA Medical Plaza,Suite 220, Los Angeles, CA 90095, USA. E-mail: mfiala@ucla.edu

doi: 10.1096/fj.201700065R

0892-6638/17/0031-0001 © FASEB 1

The FASEB Journal article fj.201700065R. Published online April 18, 2017.

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CCR2 (13). Subsequently, transplantation of bonemarrowand bone marrow–derived microglia were tested as ther-apy for neurodegenerative diseases in animalmodels andin humans, including in patients with multiple sclerosis(14); however, further discoveries have complicated thisapproach, as the origin of adultmicrogliawas shown to beprenatal from primitive myeloid progenitors in the yolksac (15).Meanwhile, in studies relevant toAD, invasion ofmonocyte-derived macrophages was noticed in the hu-man brain with ischemic plaques (16) and the AD brain(17). The investigation of brain macrophages by RNA se-quencing in a mouse model has shown that CNS macro-phages arise from yolk sac precursors during embryonicdevelopment and are not significantly related to circulat-ing myeloid cells but are activated during inflammation(18, 19). However, the inflammatory model in the animalstudy (19) has uncertain relation to monocyte and/ormacrophage infiltration of the AD brain. An extensivebody of literature shows monocyte migration across theBBB in HIV-1 encephalitis (20) that histopathologicallyresembles the AD brain (17). In an in vitro model, mono-cytes are attracted by Ab-induced chemokines to migrateacross the BBB (12).

Nonetheless, in mouse models, the role of monocyte-derivedmacrophages has remained controversial becausemonocyte invasion into theCNSwas found tobe related toradiation- or chemotherapy-inducedBBBdamage (21, 22).With the exception of patrolling circulating monocytesthat are chargedwith clearing vascularAb (23), the role ofAb clearance has been ascribed to microglia (24). How-ever, there has also been strong evidence for peripheralmonocytes playing a role in Ab clearance: 1) Ab degra-dation by mouse microglia was inefficient (25); 2) in-terference with monocyte migration by CCR2 deficiencyresulted in increased levels of cerebral Ab deposition andcognitive impairment (13); 3) CCR2 deficiency of peri-vascularmyeloid cells impairedAb clearance (26); 4) PD-1immune checkpoint blockade and regulatory T cell sup-pression increased recruitment of monocyte-derivedmacrophages in a mouse brain and cleared Ab (27, 28);and 5) in experimental autoimmune encephalitis, the ef-fective antigen presenting cells are CD45highCD11b/c+

transitional macrophages, not CD45lowCD11b/c+ micro-glia (29). Microglia are believed to clear Ab-coated Ab viathe Ab Fc domain (30, 31), but the effectiveness of Fc im-mune clearance is contradicted by poor results of Ab Abclearance (32).Conversely, therehasbeenevidence againstAb clearance by monocytes and/or macrophages in themouse model, as rapid repopulation of the brain withperipheral myeloid cells, even in the presence of anti-AbAb, failed to clear Ab plaques (33, 34).

The genetic mouse model that overexpresses theamyloid-precursor protein with pathogenic mutationsdoes not express the pathognomonic immunedefect ofAbphagocytosis bymacrophages of patients withAD (35). Inaddition, the mouse response to 1a,25-dihydroxy vitaminD3 (1,25D3) is different compared with the human re-sponse (36), and, in general, inflammatory responsesdifferbetween mice and humans (37). Finally, immune activa-tion of the hNOS2 gene is crucial in an animal modelto mimic the pathologic phenotype of AD (38). The

examination of brain tissues and immune cells fromhuman patients with AD demonstrates that the immu-nopathology and clearance of Ab depend upon mono-cytes andmacrophages (17). In theADbrain tissue assay,normal monocytes, but not AD monocytes, clear Abfromneurons (35).Monocytes that had phagocytizedAbappear fat and do not transmigrate across the BBB,whereas lean monocytes do. AD macrophages are de-fective in Ab phagocytosis and degradation and areprone to apoptosis from Ab (39); thus, in the healthybrain, monocytes may immigrate into the neuropil, clearAb by phagocytosis, and emigrate, whereas in the ADbrain, AD monocytes may not. This hypothesis is sup-ported by a study of the AD brain that shows apoptoticmacrophages that contain fibrillary Ab on the abluminalside of microvessels that circumferentially surround thecongophilic vessel wall and also colocalize with neurons(39) and plaques (17) (Fig. 1). In some patients, increasedexpression ofCD33 is associatedwith the rs3865444C riskallele for AD and decreased Ab clearance (40, 41). Theseconsiderations suggest that peripheral blood monocytesare diagnostic and therapeutic tools.

Early epidemiologic studies have pointed to the role ofinflammation because the prevalence of AD was reducedin patients who were treated with nonsteroidal anti-inflammatory drugs (42) and the brain showed the pres-ence of membrane attack complex and T cells (43). Theroles of the initiating factor of the classic complementcascade, C1q and C3 component, have been revisited inmouse models in which they were found to be associatedwith early synapse loss (44). In a recent study, macro-phages of most patients with ADdisplayed inflammatorymarkers, including CD14, TLR 2, TLR4, IL6, and CCR2, aswell asMHC-II/Ab complexes (45). Exposureofmicrogliatodocosahexaenoic acid (DHA)andeicosapentaenoic acid(EPA) decreased inflammatoryM1markers and increasedAb phagocytosis and anti-inflammatoryM2markers (46).Translation of these results to patients with MCI is notstraightforward because the inflammatory activation ofperipheral blood mononuclear cells is heterogeneous:down-regulated in a subgroup of noninflammatory pa-tients and up-regulated in a subgroup of inflammatorypatients (47, 48). The macrophage phenotype of patientswith MCI is also heterogeneous and either highly proin-flammatory M1 or very low inflammatory M2 (49). Thus,v-3 therapy should lead to an intermediate proresolutionM1-M2 phenotype, as shown in a pilot study (49).

IMMUNE THERAPIES BY RECEPTORANTAGONISTS, v-3 AND v-3–DERIVEDSPECIALIZED PRORESOLVING MEDIATORS,AND EPOXY FATTY ACIDS

Immuneapproaches in animalmodels, suchas chemokinereceptor CCR2 antagonists, purinergic receptor P2Y6 an-tagonists, or a CX3CR1 agonist (31), target single genes inCNS myeloid cells and do not consider the heterogeneityof inflammation or immune exhaustionwith deregulationof many genes and pathways in amyotrophic lateral scle-rosis (50, 51) and AD (49). Remarkably, lipid mediators

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from v-3 regulate the activation of a multitude of genesand pathways that are related to inflammation and reso-lution in vitro and in vivo (52) and provide a different ap-proach to AD therapy by multitargeting. Inflammation isnormally terminated by an active process called resolu-tion, which limits the entry of immune cells, increases theclearance of apoptotic cells by macrophage phagocytosis,and enables tissue restoration (53). Incomplete resolutionleads to unabated inflammation, which is an underlyingcause of many chronic diseases (54–56).

During the resolution of acute inflammation, host-protective mediators are biosynthesized from poly-unsaturated fatty acids (PUFA) via up-regulation of the keybiosynthetic enzyme15-lipoxygenase type 1 in leukocytes(57). This promotes the conversion of v-6 arachidonicacid to lipoxin A4 (LXA4) and of v-3 DHA to D-series

resolvins and protectins/neuroprotectins (57). DHA isalso converted in macrophages via 14-lipoxygenation tomaresins (macrophagemediators in resolving inflammation).The first identified member of this family was maresin 1(MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid). Specific members of these families ofmediators from the DHA metabolome are namedD-series resolvins [resolvin D1 (RvD1) to -6], pro-tectins (including protectin D1-neuroprotectin D1),and maresins (MaR1 and -2) and E-series resolvins(RvE1 and -2) (58). These mediators limit neutro-phil recruitment and potently stimulate macrophagephagocytosis of apoptotic cells in a stereospecificmanner. They also regulate both inflammation andchemotherapy-induced pain by inhibiting transientreceptor potential vanilloid 1 currents inneurons (59).A

THE AD Brain

Hypoglycemia, hypoxemia,dyslipidemia

Mitochondrial energy disruptionVirusesPrions

Neurotoxins

Aβ accumulationtau phosphorylation

Invading macrophages:Classical (M1)

Alternative (M2)Intermediate (M1-M2)

Disease progressionω-3 supplementation

MΦVery high M1 signature - decreased Aβ phagocytosis and disease progressionVery low M2 signature - decreased Aβ phagocytosis and disease progressionIntermediate M1-M2 signature - increased Aβ phagocytosis, decreased apoptosis

MΦ invasion across BBB

Z0-1 Disruption

Macrophage

mϕ in an Aβ plaqueMΦ Green with Aβ

Plaque (Red)

Aβ Green

MΦ (Yellow)

apoptotic perlvascular macrophages

leaky vessels

Fibrimogen

A B

a

b

c

d

a

b

c

d

Figure 1. A) Immunopathology of Alzheimer’s disease: pathogenic stimuli (a); Ab accumulation and tau phosphorylation (b);M1, -2 or M1-M2 macrophage phenotypes before modulation (c); v-3 do or do not modulate the phenotype (d); M1, -2 or M1-M2phenotypes after modulation (e). B) Immunochemistry of AD brain: macrophage invasion across BBB (a); macrophage invasionof Ab plaque (b); perivascular macrophages around congophilic vessels (c); leaky cerebral vessel (d) (17).

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novel family of macrophage-derived proresolving media-tors, called Maresins Conjugates in Tissue Regeneration,carry potent organ-protective, tissue-regenerative, and pro-resolving actions (60). In addition, protectin and resolvinsulfido-conjugates were recently identified as novelresolution mediators that control regeneration (60, 61).

Specialized proresolving mediators (SPMs) bind to theirreceptorson leukocytesandregulateanti-inflammatoryandproresolving actions. LXA4 inhibits leukocyte trafficking invivo by activating the LXA4 receptor denoted ALX/FPR2.RvD1 binds to the ALX/FPR2 receptor and another GPCRcalledGPR32, but RvD1 does not activate nuclear receptorsretinoid X receptor (RXR)-a and peroxisome proliferator-activated receptor (PPAR)-a, -d, and -g (62). RvD1 inhibitsneutrophil migration and promotes their phagocytosis bymacrophages (62). Aspirin-triggered RvD1 (AT-RvD1) in-hibits the release of IL-6 and protects the brain after surg-ical injury from neuroinflammation, synaptic dysfunction,and cognitive decline (63). RvD2 binds to GPCR GPR18and mediates bacterial phagocytosis and organ protection(64). RvE1 binds to the receptor on macrophages calledChemR23 (65), also named human chemokine-like receptor1. 13S,14S-Epoxide-maresin intermediate stimulates M1 toM2 phenotype switch (66). PD1 inhibits inflammatory cy-tokines, COX-2, and NF-kB in the CNS (67).

These SPMs are active in animal models of differentinfectious, metabolic, ischemic, arthritic, and oncogenicpathologies, such asRvD2 inmicrobial sepsis (68), RvE1 inperiodontal disease (69), PD1 in ocular herpes simplex(70), LXA4 in liver and renal fibrosis related to obesity (71),LXA4 in cerebral ischemia (72), LXA4 in brain amyloidosis(73), RvD1 in arthritis (74), and resolvins in cancer (75).Emerging studies in human participants show positivetherapeutic effects of v-3 supplementation on clot re-sorption bymacrophages of patients with coronary arterydisease (76) and on phagocytosis of Ab mentioned above(48).

v-3 PUFAs are also a source for the formation of epoxyfatty acids (EpFAs), epoxydocosapentaenoic acids fromDHA, and EETs from EPA (77) (Table 1). EpFAs areantinociceptive in several models of pain, and, like resol-vins, they dampen prostaglandin- and cytokine-driveninflammation (7, 78, 79).Of interest,v-6PUFAarachidonicacid is also a precursor to anti-inflammatory lipid media-tors that are formed in different branches of the arachi-donic acid cascade. The biologic activities of LXA4 formedby lipoxygenaseand thoseofEETsgeneratedbycytochromeP450 enzymes oppose those of prostaglandin metabolites

formedby cyclooxygenase activity on the arachidonic acidsubstrate (80). EETs are anti-inflammatory and anti-nociceptive, whereas prostaglandins and leukotrienesare inflammatory and nociceptive (81–83); however,prostaglandins are also involved in lipid-mediator classswitching in which these classic initiators of acute in-flammation switch to produce SPMs (84).

An enzyme downstream of cytochrome P450 activity,soluble epoxide hydrolase (sEH), is a master regulatingenzyme of the different EpFA metabolite classes. In-hibition of sEH stabilizes EpFAs, inhibits inflammation,and reduces pain (85). The action of EpFAs has multiplemechanisms, including interaction with the cAMP path-way (86), in addition to reduction of endoplasmic re-ticulum stress (87). In the brain, sEH inhibition and anincrease in EpFAs have reduced damage from cerebralischemia inboth aneuroprotectiveandvascularprotectivemanner (88).Of importance, EETs exert this protective rolevia glia in addition to vascular cells (89). There is evidencefrom multiple sources that high levels of sEH and a de-crease in epoxide/diol ratios is associated with vasculardementia (90) and with several psychiatric disorders, in-cluding depression (91) and schizophrenia (92).

SPMS IN THE AD BRAIN

In thebrain,DHAisaprecursor to theneuroprotectiveandanti-inflammatorymediator, PD1 (93), which is decreasedin the AD brain (94) and reduces Ab-induced neurotox-icity (95). Moreover, it has recently been shown that LXA4

wasdecreased in theADbrain andCSFand thatLXA4andRvD1 levels in the CSF positively correlate with mini-mental state examination (MMSE) scores (8), therebysuggesting a connectionwith cognitive function inAD. Inlinewith these findings, Zhu and colleagues (55) recentlyreported lower levels of MaR1, PD1, and RvD5 in theentorhinal cortex of patients with AD, thereby providingmore evidence of a disturbed resolution pathway in AD.Addition of these SPMs exerted neuroprotective activityand boosted Ab uptake by microglia, which illustratedthe feasibility of use of SPMs in a clinical setting. Indeed,supplementation with AT-RvD1 preventedmemory lossin an animal model of surgery-induced cognitive decline(63), and AT-LXA4 improved cognition in a transgenicmouse model of AD (96).

TABLE 1. PUFAs and proresolution lipid mediators

Precursor Lipid mediator Effects of lipid mediator Reference

v-3 fatty acidDHA D-series resolvins: RvD1–D6, Mar1, -2 Prophagocytic and anti-inflammatory 46EPA E-series resolvins: RvE1–E3DHA Epoxydocosapentaenoic acids Anti-inflammatory and antinociceptive 63EPA EEQ Anti-inflammatory and antinociceptive 7

v-6 fatty acidArachidonic acid LXA4 Anti-inflammatory and prophagocytic 160

EETs Anti-inflammatory and antinociceptive 7

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MACROPHAGE PHENOTYPES IN PATIENTS WITHAD AND MCI AND POLARIZATION BY v-3AND SPMS

Blood-bornemonocyte-derivedmacrophages have criticalimportance in various neurodegenerative diseases, asthese cells cross the BBB and produce specific immunepathologies in HIV-1 encephalitis (20), AD (17), andamyotrophic lateral sclerosis (97). Macrophages are bi-functional in Ab phagocytosis: in healthy individuals,they are effective in phagocytosis and the degradation ofAb, whereas in patientswithMCI andAD,macrophagesare defective in both functions (98).

Regulationof themacrophagephenotype is at the coreoftherapy for a variety of disorders, including atherosclerosis,allergy, infection, tissuerepair, obesity, emphysema, cancer,and neurodegenerative diseases (99). The extremes of amacrophage phenotype continuum in model systems aredescribed as M1 proinflammatory and M2 proresolvingand wound-healing macrophages, but in vivo intermediateand unique macrophage phenotypes are frequently found(100, 101). M1 macrophages produce cytotoxic and in-flammatory cytokines (TNF-a and IL-12), chemokines(CXCL9, -10, -11), andNOS2.M2macrophages up-regulatethe mannose receptor (Mrc1) and chitinase 3-like3 (Chi3l3).Macrophagepolarization isactivated in the followingways:1) toM1 phenotype by IFN-a/b or IFN-g signaling via IFNregulatory factor-5 (IRF5) and signal transducer and acti-vator of transcription 1 (STAT1), or alternatively by LPS viaTLR4andNF-kB signaling; 2) toM2phenotype by IL-4 andIL-13 signaling via STAT6, PPAR-g, and PPAR-d (102); IL-4induces Jmjd3-IRF4 axis to inhibit IRF5-mediated M1 po-larization (103); 3) by epigenetic changes, including thosevia a histone demethylase (104); and 4) bymiR-155 (105). Inaddition, T cells influence macrophage polarization: Th1stimulateM1 type and regulatory T cells stimulateM2 typephenotypes (106).

Defects in AD macrophage phagocytosis seem to berelated to defective protein glycosylation as a result ofdown-regulation of the enzyme, b-1,4-mannosyl-glyco-protein4-b-N-acetylglucosaminyltransferase (GlcNAc).Thisenzyme is up-regulated during Ab phagocytosis in nor-mal, but not AD, monocytes (107). Low expression ofGlcNAc is associated with poor prognosis (108). As theinhibition ofN-glycosylation decreases anti-inflammatoryand proresolution M2 macrophage polarization (109), re-duced transcription ofGlcNAcmaybe an important defectin patients with AD. b-Site amyloid precursor proteincleaving enzyme-1 is modified by bisecting GlcNAc in thebrain of patients with AD, which possibly leads to greaterb-site amyloid precursor protein cleaving enzyme-1 deg-radation and, thus, increased Ab production, as observedin a mouse model (110).

Macrophage polarization toward the proresolving M2type by SPM has a favorable effect in many disorders. v-3protect against obesity-associatedmetabolic disorders andcardiovascular disease via modulation of eicosanoid pro-duction and stimulation of anti-inflammatory action.RvD1 inhibits macrophage accumulation in adipose tis-sues and increases the proportion of alternatively acti-vated macrophages (111, 112). Resolvins, maresins, and

13S,14S-epoxy-maresin shift macrophage phenotype to aless inflammatory type (62, 113). SPMs polarize inflamma-toryM1macrophage type in amouse-air-pouchmodel to aproresolution M2 type (114). M2 macrophages have ele-vated levels of proresolving lipid mediators, includingmaresin, and decreased prostaglandins and leukotrienes inrelation to M1 macrophages (115). In addition, M2 macro-phages specificallyproduce the recently identifiedprotectinconjugate in tissue regeneration 1, which seems to be apotent novel inducer of macrophage phagocytosis (116).SPMs alsomodulate themetabolism ofmacrophages (117).

RvD1 interacts with GPCR GPR32 (62), whereas fattyacids employ PPAR-a (118–120). v-3 DHA induces M2macrophage polarization and efferocytosis via PPAR-g(121). In mouse models of AD and in vitro microglia andastrocytes, DHA has anti-inflammatory and proresolvingeffects via RXR and PPAR-g (122).

STIMULATION OF INNATE IMMUNITY BYNATURAL SUBSTANCES

In 2016, the monumental action against AD includes thedevelopment of nontoxic therapies with Abs and naturalsubstances. This approachhasgained traction after clinicalfailures and amyloid-related imaging abnormalities of AbAbs (123), which also increased cortical hyperactivity in amouse model (124). The next generations of the vaccineand Abs in development are designed to clear Ab by ac-tively or passively induced AbAbs, not by improving thefunction ofmacrophages and/ormicroglia, andmayhavevarious adverse effects on chronic administration (125).Recent Ab Ab approaches include gantenerumab (126)and aducanumab (127). Aducanumab reduced brain Aband putatively slowed clinical decline but had Ab-relatedimaging abnormalities.

Natural substances havebeenused for centuries to boostthe immune system with manifest results, such as that ob-served with curcuminoids (128) and vitamin D3 (129). De-spite extensive anecdotal experience, clinical investigationof natural substances inMCI andAD is difficult because ofthe chronic nature of these diseases that requires largeprospective studies. A large compendium of nutritionalsupplements for dementia (130) includes a cornucopia ofmicronutrients, minerals, vitamins (1,25D3 and vitamin Bcomplex), v-3 fatty acids DHA and EPA, flavonoids (e.g.,resveratrol), polyphenols (e.g., curcuminoids), and alka-loids (caffeine, ashwagandha), as well as nutraceuticals,suchasherbs,diets, andprobiotics.Currently, the followingsubstances have a potential for prevention of MCI pro-gression via increased Ab clearance on the basis of clinicalor experimental experience (131): v-3 fatty acids (48), vita-min D3 (132), vitamin B complex (133), and curcuminoids(35, 134–136).

MECHANISMS OF SPMS, 1,25D3, AND OTHERMEDIATORS THAT ENHANCE Ab PHAGOCYTOSIS

v-3 and 1,25D3 are the best-understood natural im-mune therapeutics for human use in patients with

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MCI, but their effects in patients are heterogeneous.The effects of v-3 and 1,25D3 are different from eachother and do not completely normalize the AD tran-scriptome (6). Both mediators up-regulated IL-1 innoninflammatory patients and down-regulated IL-1and IL-6 in inflammatory patients. In general, 1,25D3had more pronounced effects on normalization ofchemokine and cytokine transcription than did RvD1.1,25D3 down-regulated IL-1R1, CCL23, -2, and CD40in both groups of patients. RvD1 profoundly down-regulated NF-kB, IL-1b, CCL2, -4, and -24 in in-flammatory patients, but up-regulated IL-1a and IL-1bin noninflammatory patients. 1,25D3 forms heterodimerswith RXR and stimulates Ab phagocytosis via non-genomic signaling by increasing intracellular calciumand potentiating MEK1/2 signaling, which leads to theopening of the ClC3 channel, as well as via nuclear sig-naling (47).

Other chemicals that enhance phagocytosis in-clude bexarotene and resveratrol. Bexarotene is anRXR agonist that activates the PPAR-g and RXR het-erodimer. Bexarotene potentiates phagocytosis of Abin an animal model (137, 138), but this has been onlyincompletely reproduced in other laboratories (139).Resveratrol altered certain CSF biomarkers (Ab1–40)without consistent cognitive changes in a controlledclinical trial (140). Resveratrol has a broad spectrumof activities against Ab and t neuropathologies, in-cluding attenuation of inflammatory mechanismsand increasing intracellular Ab clearance, in part byactivating autophagy and proteolysis viamodulationof the AMPK/sirtuin1/PPAR-g coactivator1-a sig-naling network (141). PPAR-g coactivator1-a is atranscriptional coactivator that regulates the genesthat are involved in energy metabolism and mito-chondrial biogenesis and function and induces po-larization of macrophages toward M2 via STAT6/PPAR-g (142).

OBSERVATIONAL STUDIES AND CLINICALTRIALS OF v-3: COGNITIVE, IMMUNE, ANDMOLECULAR EFFECTS

Retrospective epidemiologic studies in various pop-ulations have shown positive cognitive results in relationto optimal DHA plasma levels or a high consumption offish in 14 of 17 studies (143). In a controlled study of v-3supplementation, patients with MCI with MMSE score.27 reduced cognitive decline compared with placebo(144). v-3 supplementation in a double-blind study im-proved memory functions in healthy older adults (145).Recently, 3 trials (144–147)were analyzed according to theCochrane Handbook for Systematic Reviews of Interven-tions and found no evidence for the efficacy of v-3 sup-plements in the treatment of mild to moderate AD (148).Seafood consumption ($1 meal/wk) was significantlycorrelated with less AD pathology, but this effect wasobserved only among apolipoprotein E (APOE) e4 carriers(149). The choice of fish-derived DHA vs. algal DHA hasnot been considered an issue, but the 2 largest clinical trials

of DHA supplementation had different results: fish-derived DHA showed the slowing of decline in patientswith early MCI, whereas algal DHA was not differentfrom placebo.

A recent observational study of supplementation bythe v-3 drink, Smartfish (Smartfish, Oslo, Norway),analyzed the immune and molecular effects of v-3supplementation in patients with MCI. This drink is awell-characterized, stabilized emulsion of v-3 lipids,antioxidants, vitamin D3, whey protein, and resvera-trol. This small study showed significant enhancementof Ab phagocytosis after only 1 mo in parallel withcognitive stabilization (48). Immune improvementwas marred in some patients by lack of daily compli-ance, infections, diabetes mellitus, cancer, and sur-geries. RvD1 increased in macrophages in 80% ofpatients with MCI. v-3 regulated the inflammatoryactivation of peripheral blood mononuclear cells—either too high or too low at baseline—into a middlegreen zone (48). This study has been recently extendedto 14.7 mo (average follow-up) (49). The results haveshown that macrophage M1 or -2 type at baseline wasmodulated in v-3–supplemented APOEe3/e3 patientsto an intermediate type M1-M2 with improved Abphagocytosis, whereas macrophages of APOEe3/e4patients were modulated in an irregular fashion. Ofimportance, MMSE score significantly increased inAPOEe3/e3 patients (by 2.2 points/yr) vs. no increasein APOEe3/e4 patients (0 points/yr) (49).

DESIGN OF AN IDEAL CLINICAL TRIAL OFv-3 SUPPLEMENTATION

It is clear that MCI and AD involve the deregulation ofmany pathways and thus requires combination therapy,as suggested by the glimmers of success with this ap-proach (150). Effective therapy should be based on v-3 ofthe highest quality, protected against oxidation [v-3 areoxidized in 50%of commercial supplements (151)]. It is notclearwhether there are advantages of fish-derivedvs. algalv-3 and whether DHA, EPA, or both are needed. Wheyprotein is necessary for emulsification and nutrient de-livery (152). Additional natural supplements with centraland peripheral immune effects, such as resveratrol (153),vitamin D3 (154), vitamin B complex (folic acid, vitaminsB6 and B12) (155), and curcumin (35), should be evaluatedfor inclusion in the supplement. The design should berandomized, placebo-controlled, anddouble-blind,with asample size of adequate power. Participants should beobserved in 2-mo intervals and comorbidities, such asfractures, infections, and cancer, whichmay interfere withthe immune response, must be analyzed. As it is impos-sible to know the genotype in advance of trial enrollment,results must be analyzed according to the APOEe3/e3 vs.e3/e4 genotype. Use of over-the-counter supplementsshould be discontinued. According to the results of ourrecent trial of v-3 (49), we estimate that in APOEe3/e3patientswithMCI, the effectof Smartfish supplementationonMMSE could be 60–70% greater than that of a placebo.This is more likely to be achieved if patients follow

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recommendations for physical and mental exercise, ade-quate sleep, and eating a diet low in saturated fat and highin fish (156). Assuming 60% effect, we calculated thesample size in a study with a 2-yr follow-up (with 80%power, a = 0.05) as 30 patients on v-3 preparation and 30controls on a placebo in an ideal situation with identicalproportion of APOEe3/e3 vs. e3/e4 genotype subjects;however, the APOE genotype distribution cannot be esti-mated in advance in small samples. Therefore, the numberof the participants in the trial should be at least 2 or 3 timeshigher. Trials of mAbs against Ab required 2000 patients(157, 158) and still failed; however, even a small-size(100–200 participants) trial of v-3 preparation will de-finitively produce a wealth of data on immune responsesthatmay explainwhy certain patients respond cognitivelybetter than others.

CONCLUSIONS

A retrospective (143) and a prospective study (144) dem-onstrated cognitive benefits with v-3 supplementation.Our observational study with the v-3 drink suggests thatthe beneficial effects are associated with macrophage po-larization to M1-M2 type, particularly in APOe3/e3 pa-tients (49). Conversely, 2 large prospective studies seem todisclaim the benefits of v-3 because oral supplementationwith algal DHA (but without antioxidants and othercomponents) had no effect on the cognitive function inpatients who were at risk of macular degeneration (159)and in those with AD (146). The benefits of v-3 need to beconfirmed in a randomized controlled trial that will ana-lyze not only the overall cognitive results but also baselinecognitive and health status, APOE type, compliance (i.e., areliable caregiver), intercurrent inflammatory and immu-nosuppressiveconditions, andcorrelationof cognitiveandimmune results during the trial.

ACKNOWLEDGMENTS

Studies of innate immunity in AD and MCI were supportedby a grant from the Alzheimer’s Association and a donationfrom Smartfish AS. Smartfish AS supplied the drink to patientswho requested it, but was not involved in the design, analysis,interpretation of the data, or the decision to submit themanuscript for publication. M.F. received paid travel tomeetings and honoraria from Smartfish AS. G.K. receivedsupport from the Dutch MS Research Foundation (14-878MS). B.H. and K.W. were supported by U.S. National Institutesof Health, National Institute of Environmental Health SciencesGrant R01-ES002710, and K.W. by Grant 5T32L086350-08. Theauthors thank J. Gornbein (Department of Biomathematics,University of California Los Angeles) for calculating thesample size of the v-3 study.

AUTHOR CONTRIBUTIONS

M.FialaandM.Pellegrini reviewedv-3 studies inmacrophagesand human patients; G. Kooij reviewed specialized pro-resolving mediators; and K. Wagner and B. Hummockreviewed epoxy fatty acids.

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Received for publication January 27, 2017.Accepted for publication April 5, 2017.

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