Nutrients, Microglia Aging, and Brain Aging

Review ArticleNutrients Microglia Aging and Brain Aging

Zhou Wu1 Janchun Yu2 Aiqin Zhu3 and Hiroshi Nakanishi1

1Department of Aging Science and Pharmacology Faculty of Dental Science Kyushu University Fukuoka 812-8582 Japan2Department of General Surgery Peking UnionMedical College Hospital Chinese Academy ofMedical Sciences Beijing 100730 China3Institution of Geriatric Qinghai Provincial Hospital Xining 810007 China

Correspondence should be addressed to Zhou Wu zhouwdentkyushu-uacjp and Janchun Yu yujianchun2000hotmailcom

Received 25 September 2015 Revised 21 December 2015 Accepted 31 December 2015

Academic Editor Trevor A Mori

Copyright copy 2016 Zhou Wu et alThis is an open access article distributed under theCreative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

As the life expectancy continues to increase the cognitive decline associated with Alzheimerrsquos disease (AD) becomes a big majorissue in the world After cellular activation upon systemic inflammation microglia the resident immune cells in the brain start torelease proinflammatory mediators to trigger neuroinflammation We have found that chronic systemic inflammatory challengesinduce differential age-dependent microglial responses which are in line with the impairment of learning and memory even inmiddle-aged animals We thus raise the concept of ldquomicroglia agingrdquo This concept is based on the fact that microglia are thekey contributor to the acceleration of cognitive decline which is the major sign of brain aging On the other hand inflammationinduces oxidative stress and DNA damage which leads to the overproduction of reactive oxygen species by the numerous types ofcells including macrophages and microglia Oxidative stress-damaged cells successively produce larger amounts of inflammatorymediators to promote microglia aging Nutrients are necessary for maintaining general health including the health of brain Theintake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive declineduring aging We herein review our microglia aging concept and discuss systemic inflammation and microglia aging We proposethat a nutritional approach to controlling microglia aging will open a new window for healthy brain aging

1 Introduction

The cognitive decline associated with aging and Alzheimerrsquosdisease (AD) will be a major issue in aging societies aroundthe world as the life expectancy continues to increaseA better understanding of the factors that accelerate thiscognitive decline will help in the development of strategiesfor preventing or delaying this cognitive decline Microgliathe resident mononuclear phagocytes in the brain are chron-ically or pathologically activated to influence the neuronalenvironment There is increasing evidence that activatedmicroglia produce excessive reactive oxygen species (ROS)during aging [1] and hypoxia [2ndash6] resulting in the nuclearfactor-120581B- (NF-120581B-) dependent excessive production ofproinflammatory mediators including interleukin-1120573 (IL-1120573) tumor necrosis factor-120572 (TNF-120572) and interleukin-6 (IL-6) [7ndash11] Furthermore activated microglia-mediated neu-roinflammation is closely associated with the pathogenesisof AD pathogenesis [12] because activated microglia trigger

neuroinflammation to promote neuronal damage and thedeposition of amyloid 120573 (A120573) [13 14] Moreover anti-inflammatory agents improve the cognitive functions of ADpatients [15 16]

It is well accepted that chronic systemic inflammation canalter the neuroinflammation in the brain [17 18] In additionto being associated with systemic diseases such as atheroscle-rosis and diabetes rheumatoid arthritis (RA) periodontitisand inflammatory bowel disease (IBD) also directly initiateor hasten the progression of AD [19] A clinical study hasdemonstrated the impact of RA and periodontitis on AD[20] and recent experimental studies have clarified the routesof inflammatory signal transduction from chronic systemicinflammation to the brain [17 18 20]

We have recently found that natural products such aspropolis inhibit the hypoxia-induced production of proin-flammatory mediators by microglia through the inhibitionofmitochondria-derived ROS generation and the subsequentactivation of the NF-120581B signaling pathway Furthermore we

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 7498528 9 pageshttpdxdoiorg10115520167498528

2 Oxidative Medicine and Cellular Longevity

have found that RNSP a traditional Tibetan medicine whichis composed of 70 herbal components improves the cognitivefunction in middle-to-moderate AD patients living at highaltitude by reducing the levels of proinflammatory mediatorsand the deposition of A120573 [21] In the present review we willhighlight our proposed concept of microglia aging whichrefers to the fact that microglia are the potent acceleratorsof brain aging due to their induction of cognitive declineWe will also discuss the benefits of nutrients in preventingmicroglia aging and cognitive decline

2 The Risk of Systemic InflammatoryDiseases for AD

RA is a chronic inflammatory bone disorder which causesjoint damage A postmortem survey found that the preva-lence of AD was reduced in RA patients who were long-term users of nonsteroidal anti-inflammatory agents [22ndash25]More recently patients with midlife RA were confirmed tohave an increased risk of cognitive impairment over a 21-year follow-up study in several case-control andhospital- andregister-based studies that were performed to examine theassociation between RAarthritis and dementiaAD [26]

Periodontitis is a chronic inflammatory disorder in theperiodontal tissuesThere is growing clinical evidence to sup-port a close link between periodontitis and the developmentand progression of AD [27 28] More recently the threemajor periodontal bacteria ldquoRed complexrdquo including Tre-ponema denticola Tannerella forsythia and Porphyromonasgingivalis and their components have been detected in thebrain of AD patients [29 30] More details have beenreviewed by us recently [20]

IBD is a chronic inflammatory disorder in the gutThe gutbacteria are important for inducing systemic inflammationand LPS is a potentially associated mediator which migratesinto the intestinal capillaries [31] Indeed elevated LPSconcentrations can be found in the plasma of AD patients[32ndash34] which supports a possible role of LPS in the pro-motion of neuroinflammation and the triggering cognitivedecline [35ndash37] Furthermore the chronically inflamed gutgenerates systemic proinflammatory cytokines to promoteneuroinflammation which causes cognitive decline [38 39]

3 Oxidative Damage in SystemicInflammatory Diseases and AD

31 Oxidative Damage in the Chronic Inflammatory DisordersROS contribute to the progression of chronic inflammatorybone disorders including RA and periodontitis The inflam-matory cell-mediated overproduction of TNF-120572 is thought tobe the main contributor to the increased release of ROS inRA patients [40] because TNF-120572 not only causes cell damagebut also inhibits antioxidants such as superoxide dismutase 1(SOD1) and SOD3 [41 42] Numerous studies have indicatedexcess ROS levels and the depletion of antioxidant levelsin the gingival crevicular fluid [43 44] There is furtherevidence of higher levels of lipid peroxidation hydrogenperoxides and oxidative DNA damage in animal models of

periodontitis [45] Indeed periodontitis is associated withsystemic oxidative stress and a reduced global antioxidantcapacity which suggests that oxidative stress in patientswith periodontitis could be closely linked to the biomarkerof inflammation including C-reactive protein [46] It isconsidered that ROS are involved in the chronic inflam-matory bone disorders by regulating osteoblasts and osteo-clasts [47] because the increasedmitochondria-derived ROSespecially H

2O2 reduces the differentiation and maturation

of osteoblasts by inhibiting type 1 collagen and alkalinephosphatase colony-forming unit-osteoprogenitor forma-tion and Runt-related transcription factor 2 activation [4849] On the other hand the increased ROS enhance theosteoclast numbers and resorption by stimulating receptoractivator of NF-120581B ligand and TNF-120572 expression throughextracellular-signal-regulated kinase and NF-120581B activation[50]

ROS are increased in the colonic mucosa of patientswith the alterations in the mucosal antioxidant defenses inIBD patients [51 52] because the bodyrsquos major antioxidantglutathione is depleted but its oxidized form glutathionedisulfide is increased in individuals with active IBD [53 54]The imbalance caused by the increase of ROS productionand the decrease of antioxidant capacity-induced oxidativestress is considered to be themajor pathogenic mechanism ofIBD [55 56] Excessive levels of ROS result in damage to thecytoskeleton protein including the temporal disruption ofthe barrier integrity and increasing gut permeability [57 58]Therefore ROS promote oxidative damage modulate theintra- and extracellular redox status and interfere with theactivation of proteolytic enzymes in the systemic inflamma-tory environment

32 Oxidative Damage in AD Oxidative stress is consideredto be the main cause of AD In microglia mitochondrialdysfunction leads to the excess production of ROS whichpromotes the redox imbalance and stimulates proinflamma-tory gene transcription and the release of cytokines suchas IL-1 IL-6 and TNF-120572 thereby inducing neuroinflam-mation The neuroinflammation-prolonged oxidative stressleads to the accumulation of A120573 and tau phosphorylationand then induces neurotoxicity in AD patients [59 60]Thus microglia-mediated neuroinflammation is perceived asa cause and a consequence of chronic oxidative stress

Extensive oxidative stress is observed in all of the cellularmacromolecules of AD patients First lipid peroxidationis greatly enhanced in AD The 4-hydroxynonal levels aresignificantly elevated in the hippocampus entorhinal cor-tex temporal cortex amygdala parahippocampal gyrus andventricular fluid [61ndash64] and plasma [65] of AD patientsSecond the oxidative modification of proteins which resultsfrom either a direct ROS attack or from the reactions thatoccur through the binding of glycation glycoxidation andlipid peroxidation products has been extensively shown inADThemost widely studiedmarkers of protein oxidation areprotein carbonyls and 3-nitrotyrosine Significant increases ofprotein carbonyl are observed in the hippocampus parietallobe and superior middle temporal gyrus of AD patients[66 67] Third oxidative damage occurs in the DNARNA

Oxidative Medicine and Cellular Longevity 3

of AD patients High levels of DNA breaks are found in thehippocampus and cerebral cortex of AD patients [68] 8-Hydroxydeoxyguanosine (8-OHdG) is the most widely usedDNA oxidative marker which is increased in ventricularcerebrospinal fluid [69] and the peripheral tissues such assporadic fibroblasts [70] and in the lymphocytes of ADpatients [71]

It has been demonstrated that the onset of AD is com-monly preceded by an interim phase known asmild cognitiveimpairment (MCI) when there is no significant increasein senile plaques [72ndash74] MCI patients exhibit significantoxidative imbalance in comparison to age-matched controlssince the elevation of overall protein peroxidation and theoxidative modification of specific proteins are detected in thebrain including hippocampus [75 76] and reduction of theactivity of antioxidant enzymes such as superoxide dismutaseglutathione peroxidase and glutathione is observed in MCIpatients [77 78] These facts strongly suggest that the oxida-tive imbalance appears at the very early stage of AD

Chronic systemic inflammation links to neuroinflamma-tion by the releasing of proinflammatorymediators includingIL-1120573 to activate microglia [17 18] Repeated LPS-inducedchronic systemic inflammation in mice induces microglialactivation and prolonged IL-1120573 production by activatedmicroglia [79] Furthermore systemic inflammatory chal-lenge in the late gestation of mice increases the depositionof A120573 and tau phosphorylation which resulted in the impair-ment of working memory during adult [36]

The four routes by which systemic immune signals canbe transmitted to the brain have been intensively studied[17 18] In addition to these four classical routes we haverecently found that the leptomeningeal cells which cover thesurface of the brain parenchyma release the proinflammatorycytokines to activatemicroglia during systemic inflammatorychallenge [80 81] Therefore leptomeningeal cells can trans-mit signals from systemic immune cells to microglia

4 Microglia Aging ConceptMicroglia and Brain Aging

As the phagocytic cells in the brain microglia are primedduring aging even in middle age The primed microgliacan produce an exaggerated inflammatory response inthe brain because age-dependent dysfunctions of lysoso-malmitochondria system allow for the hypergeneration ofROS The increased intracellular ROS then activates theredox-sensitive transcription factors including NF-120581B toprovoke exaggerated inflammatory responses [1] The sen-sitivity to oxidative stress and activation of redox-sensitivetranscription factors during aging may drive the emergenceof senescent-type microglia (microglia aging) This mayexplain why A120573 which cannot sufficiently activate NF-120581B isable to induce IL-1120573 secretion by activated microglia isolatedfrom the aged mouse brain but not from the young adultmouse brain [82]

It is noted that chronic systemic inflammation inducesage-dependent differential responses in microglia The acti-vated microglia produce anti-inflammatory mediators in

young adult adjuvant arthritis (AA) rats an animal model ofRA [18 80 81] However the activated microglia producedproinflammatory mediators in the middle-aged AA rats [83]Therefore chronic systemic inflammation induces microgliaaging from middle age Furthermore the microglia aginginduces the functional outcomes during systemic inflamma-tion The long-term potentiation (LTP) a cellular substrateinvolved in learning and memory in the hippocampus issignificantly decreased in middle-aged AA rats but not inyoung adult rats The systemic administration of minocy-cline a known inhibitor of microglial activation significantlyrestores the formation of LTP in middle-aged AA rats Theseobservations suggest that chronic systemic inflammationinduces deficits of learning and memory through microgliaaging [84]

Microglia is highly sensitive to excessive ROS activatedNF-120581B due to the increased oxidative mitochondrial DNA(mtDNA) damage [1] The hypoxia activates the NF-120581B sig-naling pathway to induce microglia aging [6ndash8 11] Further-more microglia are recognized as the major cells for NF-120581B-dependent proinflammatory mediators production duringstroke the most common form of hypoxia-ischemic braininjury [85 86] The microglia aging mediated neuroinflam-matory responses are closely associatedwith the pathogenesisof AD [12] because the proinflammatory mediators promoteneuronal cell damage and excessive A120573 deposition [12 87]These observations suggest that the microglia aging is animportant causative factor for AD

5 Nutrients in Microglia Aging andCognitive Function

51 Propolis There is increasing evidence that natural nutri-ents can provide significant benefits in dementia patients[88] Propolis is a resinous substance which is produced byhoney as defense against intruders It has been used thera-peutically since ancient times The chemical composition ofpropolis depends on the local floral at the site of collection[89ndash91] In addition to the fact that propolis has antioxidativeand anti-inflammatory effects [92ndash94] we recently found thatpropolis significantly inhibits the secretion of IL-1120573 TNF-120572 and IL-6 by microglia by inhibition of the activationof NF-120581B signaling pathway [11] Moreover propolis wasobserved to significantly inhibit the increased generationof mitochondria-derived ROS which is responsible for theactivation of NF-120581B signaling pathway Moreover propolissignificantly inhibits the increased expression of 8-OHdGa biomarker for oxidative DNA damage [95] mainly in themitochondria of microglia after hypoxia Since oxidativemtDNA damage impairs the respiratory chain to form avicious cycle which promotes ROS generation [1] propolismay prevent and reverse microglia aging through its antiox-idant property both systemically and in the brain [92ndash96](Figure 1)

52 RNSP RNSP is one of the Tibetan medicines composedof 70 natural components It is used clinically for treatingcerebrovascular diseases cerebral infarction and epilepsy


Young Middle Aged

Systemic inflammation(RA periodontal diseases IBD)

Microglia aging

NeuroinflammationIL-1120573

Cognitive decline

ROS

Anti-inflammationIL-10

ROS

Nutrients (propolis RNSP vitamins omega-3 fatty acids)

Slow brain aging

Figure 1 A schematic representation of the preventing and reversal of microglia aging by the antioxidant nutrients Increased microglialmitochondria-derived ROS induce neuroinflammation which initiates cognitive decline during aging Chronic systemic inflammationpromotes microglia aging even in middle age through excessive neuroinflammation The oral intake of antioxidant nutrients includingpropolis RNSP vitamins and omega-3 fatty acids will prevent and reversemicroglia aging thereby improving cognitive function and slowingbrain aging

and brain concussion Our previous studies showed thatRNSP improves learning and memory in a mouse model ofAD (Tg2576) [21 97] and improves the cognitive functionsin mild-to-moderate AD patients living at high altitude[98] Furthermore RNSP reduces proinflammatory medi-ators including IL-1120573 TNF-120572 and IL-6 in the activatedmacrophages and serum in humans indicating that it alsoameliorates the systemic inflammation [98 99]

53 Other Nutrients As a concept which was first introducedin 1985 oxidative stress is used to describe a condition ofimbalance between oxidants and antioxidants in favor ofoxidants which potentially leads to cellular damage [100 101]Oxidative stress induces the oxidation of DNA proteinsand lipids Through detection of 8-OHdG a marker ofoxidative damage to DNA increased mtDNA damage inthe parietal cortex of AD patients was shown indicatingthat mtDNA is particularly sensitive to oxidative damage[102] Furthermore the intake of antioxidants in patients withMCI was considered to be helpful in lowering the risk ofconversion to cognitive impairment because MCI representsa prodromal stage of AD and oxidative damage appears tooccur as one of the earliest pathophysiological events in AD[103 104]

Studies have shown the roles of the antioxidant nutrientsin microglial activation It was reported that 125(OH)

2D3

inhibited the production of TNF-120572 IL-6 and NO by thestimulated microglia in a concentration-dependent mannerbecause vitamin D3 receptors are expressed in microglia[105] Another report showed that vitamin E might provideneuroprotection in vivo by attenuating microglial TNF-120572and NO production by suppressing the microglial activationof p38 mitogen-activated protein kinase and NF-120581B [106]Furthermore vitamin E reduces the LPS-induced increase inROS and IL-6 in the primary microglia and the intraperi-toneal injection of LPS has been shown to induce lipidperoxidation and IL-6 in the brain [107] On the otherhand another study showed dramatic microglial activation

particularly in the CA1 region of the hippocampus [108]More recent research showed that vitamin D deficiencydecreases the release of TNF-120572 and IL-6 in culturedmicrogliaupon stimulation with Toll-like receptor agonists [109] Theroles of n-3 fatty acids such as docosahexaenoic acid (DHA)and eicosapentaenoic acid (EPA) in microglial activationhave also been reported It was noted that DHA and EPAdecreased the inflammatory responses and increased the anti-inflammatory responses ofmicroglia after the phagocytosis ofA12057342 and thatDHAdecreasedTNF-120572 production while EPAincreased production of brain derived neurotrophic factorin cultured human CHME3 microglial cells [110] A morerecent study showed that DHA and EPA inhibited the releaseof TNF-120572 and NO from primary microglia which occurs inresponse to interferon-120574 and myelin stimulation [111]

A great deal of evidence exists to support the rolesof antioxidant nutrients in cognitive function Vitamin Ehas been reported to improve cognitive function in elderlyindividuals [112] It is known that the soluble A120573 oligomerscause cognitive loss and synaptic dysfunction in AD patientsThe treatment with vitamin C for 6 months attenuatedA120573 oligomer formation restored the reduced synaptophysinlevel and mitigated the memory behavioral decline in anAD mouse model [113] More recent research showed thatvitamins C and E supplementation mitigated the melamine-induced impairment of hippocampal synaptic plasticity [114]However other studies did not find evidence to support theefficacy of vitamin E B-6 or B-12 as a preventive therapyor treatment in individuals with AD or MCI [115 116] and12 months of vitamins E and C supplementation did notimprove the mini-mental state examination score of elderlyindividuals in Iran [117] The potential role of DHA andEPA in the prevention of cognitive decline including thedecline associated with AD has attracted major interest overthe past 20 years Recent research showed that n-3 fattyacids supplementation ameliorated memory deficits whichincreased the serum total antioxidant capacity [118] On theother hand EPA and DHA supplementation for 2 years was


not found to affect the cognitive decline in healthy elderlyindividuals [119] Further intervention studies with largerstudy populations should be undertaken to identify the roleof antioxidants in the management of cognitive function

Approaches with multiple antioxidant nutrients to blockthe oxidative stress related to the systemic and brain inflam-mation pathwaysmay therefore prevent or delay the cognitiveimpairment associated with AD by preventing microgliaaging

6 Conclusion

We herein provided the concept of microglia aging as a brainaging accelerator which is associated with cognitive declineduring aging and in AD Chronic systemic inflammationpromotes microglia aging even at middle age Certain nutri-ents may therefore be beneficial for delaying brain aging bypreventing or reversing microglia aging (Figure 1)

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Zhou Wu and Janchun Yu contributed equally to this work

Acknowledgment

This work was supported by a Yamada Research Grant toZhou Wu (no 0183)

References

[1] H Nakanishi and Z Wu ldquoMicroglia-aging roles of microgliallysosome- andmitochondria-derived reactive oxygen species inbrain agingrdquo Behavioural Brain Research vol 201 no 1 pp 1ndash72009

[2] C Kaur and E A Ling ldquoPeriventricular white matter damagein the hypoxic neonatal brain role of microglial cellsrdquo Progressin Neurobiology vol 87 no 4 pp 264ndash280 2009

[3] C Kaur V Sivakumar G W Yip and E A Ling ldquoExpressionof syndecan-2 in the amoeboid microglial cells and its involve-ment in inflammation in the hypoxic developing brainrdquo GLIAvol 57 no 3 pp 336ndash349 2009

[4] G Rathnasamy E-A Ling and C Kaur ldquoIron and ironregulatory proteins in amoeboid microglial cells are linked tooligodendrocyte death in hypoxic neonatal rat periventricularwhitematter through production of proinflammatory cytokinesand reactive oxygennitrogen speciesrdquo The Journal of Neuro-science vol 31 no 49 pp 17982ndash17995 2011

[5] L Yao E M Kan J Lu et al ldquoToll-like receptor 4 mediatesmicroglial activation and production of inflammatory medi-ators in neonatal rat brain following hypoxia Role of TLR4in hypoxic microgliardquo Journal of Neuroinflammation vol 10article 23 2013

[6] C Kaur V Sivakumar Z Zou and E-A Ling ldquoMicroglia-derived proinflammatory cytokines tumor necrosis factor-120572

and interleukin-1120573 induce Purkinje neuronal apoptosis via theirreceptors in hypoxic neonatal rat brainrdquo Brain Structure andFunction vol 219 no 1 pp 151ndash170 2014

[7] F Fabbri S Carloni G Brigliadori W Zoli R Lapalombellaand M Marini ldquoSequential events of apoptosis involvingdocetaxel a microtubule-interfering agent a cytometric studyrdquoBMC Cell Biology vol 7 article 6 2006

[8] S Carloni E Mazzoni M Cimino et al ldquoSimvastatin reducescaspase-3 activation and inflammatory markers induced byhypoxia-ischemia in the newborn ratrdquo Neurobiology of Diseasevol 21 no 1 pp 119ndash126 2006

[9] YDeng J Lu V Sivakumar E A Ling andC Kaur ldquoAmoeboidmicroglia in the periventricular white matter induce oligo-dendrocyte damage through expression of proinflammatorycytokines via MAP kinase signaling pathway in hypoxic neona-tal ratsrdquo Brain Pathology vol 18 no 3 pp 387ndash400 2008

[10] V Sivakumar W S Foulds C D Luu E-A Ling and C KaurldquoRetinal ganglion cell death is induced by microglia derivedpro-inflammatory cytokines in the hypoxic neonatal retinardquoThe Journal of Pathology vol 224 no 2 pp 245ndash260 2011

[11] ZWu A Zhu F Takayama et al ldquoBrazilian green propolis sup-presses the hypoxia-induced neuroinflammatory responses byinhibiting NF-120581B activation in microgliardquo Oxidative Medicineand Cellular Longevity vol 2013 Article ID 906726 10 pages2013

[12] E G McGeer and P L McGeer ldquoInflammatory processesin Alzheimerrsquos diseaserdquo Progress in Neuro-Psychopharmacologyand Biological Psychiatry vol 27 no 5 pp 741ndash749 2003

[13] M Yamamoto T Kiyota M Horiba et al ldquoInterferon-120574 andtumor necrosis factor-120572 regulate amyloid-120573 plaque depositionand 120573-secretase expression in Swedish mutant APP transgenicmicerdquo The American Journal of Pathology vol 170 no 2 pp680ndash692 2007

[14] Y-F Liaoi B-JWang H-T Cheng L-H Kuo andM SWolfeldquoTumor necrosis factor-120572 interleukin-1120573 and interferon-120574stimulate 120574-secretase-mediated cleavage of amyloid precursorprotein through a JNK-dependentMAPKpathwayrdquoThe Journalof Biological Chemistry vol 279 no 47 pp 49523ndash49532 2004

[15] ADAPT Research Group C L Meinert L D McCaffrey and JC Breitner ldquoAlzheimerrsquos disease anti-inflammatory preventiontrial design methods and baseline resultsrdquo Alzheimerrsquos ampDementia vol 5 no 2 pp 93ndash104 2009

[16] W J Lukiw and N G Bazan ldquoNeuroinflammatory signalingupregulation in Alzheimerrsquos diseaserdquo Neurochemical Researchvol 25 no 9-10 pp 1173ndash1184 2000

[17] V H Perry T A Newman and C Cunningham ldquoThe impactof systemic infection on the progression of neurodegenerativediseaserdquo Nature Reviews Neuroscience vol 4 no 2 pp 103ndash1122003

[18] V H Perry ldquoThe influence of systemic inflammation on inflam-mation in the brain implications for chronic neurodegenerativediseaserdquo Brain Behavior and Immunity vol 18 no 5 pp 407ndash413 2004

[19] N Pischon N Heng J-P Bernimoulin B-M Kleber S NWillich and T Pischon ldquoObesity inflammation and periodon-tal diseaserdquo Journal of Dental Research vol 86 no 5 pp 400ndash409 2007

[20] Z Wu and H Nakanishi ldquoConnection between periodontitisand Alzheimerrsquos disease possible roles of microglia and lep-tomeningeal cellsrdquo Journal of Pharmacological Sciences vol 126no 1 pp 8ndash13 2014


[21] A-Q Zhu Y-D Chu Q-X Li and C L Masters ldquoTibet-medicine effects on 120573-amyloid pathology in a transgenic mousemodel of Alzheimerrsquos diseaserdquo Chinese Pharmacological Bul-letin vol 25 no 6 pp 720ndash724 2009

[22] P L Mcgeer E Mcgeer J Rogers and J Sibley ldquoAnti-inflammatory drugs and Alzheimer diseaserdquo The Lancet vol335 no 8696 p 1037 1990

[23] P L McGeer M Schulzer and E G McGeer ldquoArthritis andanti-inflammatory agents as possible protective factors forAlzheimerrsquos disease a review of 17 epidemiologic studiesrdquoNeurology vol 47 no 2 pp 425ndash432 1996

[24] B A Inrsquot Veld A Ruitenberg A Hofman et al ldquoNonsteroidalanti-inflammatory drugs and the risk of Alzheimerrsquos diseaserdquoThe New England Journal of Medicine vol 345 no 21 pp 1515ndash1521 2001

[25] C A Szekely J E Thorne P P Zandi et al ldquoNonsteroidal anti-inflammatory drugs for the prevention of Alzheimerrsquos diseasea systematic reviewrdquo Neuroepidemiology vol 23 no 4 pp 159ndash169 2004

[26] K Wallin A Solomon I Kareholt J Tuomilehto H Soininenand K Walin ldquoMidlife rheumatoid arthritis increases the riskof cognitive impairment two decades later a population-basedstudyrdquo Journal of Alzheimerrsquos Disease vol 31 no 3 pp 669ndash6762012

[27] J M Noble L N Borrell P N Papapanou M S V ElkindN Scarmeas and C B Wright ldquoPeriodontitis is associatedwith cognitive impairment among older adults analysis ofNHANES-IIIrdquo Journal of Neurology Neurosurgery and Psychi-atry vol 80 no 11 pp 1206ndash1211 2009

[28] P S Stein M J Steffen C Smith et al ldquoSerum antibodies toperiodontal pathogens are a risk factor for Alzheimerrsquos diseaserdquoAlzheimerrsquos and Dementia vol 8 no 3 pp 196ndash203 2012

[29] S Poole S K Singhrao L Kesavalu M A Curtis and SCrean ldquoDetermining the presence of periodontopathic viru-lence factors in short-term postmortem Alzheimerrsquos diseasebrain tissuerdquo Journal of Alzheimerrsquos Disease vol 36 no 4 pp665ndash677 2013

[30] G Riviere K H Riviere and K S Smith ldquoMolecular andimmunological evidence of oral Treponema in the humanbrain and their association with Alzheimerrsquos diseaserdquo OralMicrobiology and Immunology vol 17 no 2 pp 113ndash118 2002

[31] M D Neal C Leaphart R Levy et al ldquoEnterocyte TLR4mediates phagocytosis and translocation of bacteria across theintestinal barrierrdquoThe Journal of Immunology vol 176 no 5 pp3070ndash3079 2006

[32] R Zhang R G Miller R Gascon et al ldquoCirculating endotoxinand systemic immune activation in sporadic amyotrophiclateral sclerosis (sALS)rdquo Journal of Neuroimmunology vol 206no 1-2 pp 121ndash124 2009

[33] R Zhang R G Miller C Madison et al ldquoSystemic immunesystem alterations in early stages of Alzheimerrsquos diseaserdquo Journalof Neuroimmunology vol 256 no 1-2 pp 38ndash42 2013

[34] J R Hall A R Wiechmann L A Johnson et al ldquoBiomarkersof vascular risk systemic inflammation and microvascularpathology and neuropsychiatric symptoms in Alzheimerrsquos dis-easerdquo Journal of Alzheimerrsquos Disease vol 35 no 2 pp 363ndash3712013

[35] M J Engelhart M I Geerlings J Meijer et al ldquoInflammatoryproteins in plasma and the risk of dementia the rotterdamstudyrdquo Archives of Neurology vol 61 no 5 pp 668ndash672 2004

[36] D Krstic A Madhusudan J Doehner et al ldquoSystemic immunechallenges trigger and drive Alzheimer-like neuropathology inmicerdquo Journal of Neuroinflammation vol 9 article 151 2012

[37] J J M Hoozemans A J M Rozemuller E S van HaastertP Eikelenboom and W A van Gool ldquoNeuroinflammation inAlzheimerrsquos disease wanes with agerdquo Journal of Neuroinflamma-tion vol 8 article 171 2011

[38] P Eikelenboom E Van Exel J JMHoozemans R Veerhuis AJ M Rozemuller and W A Van Gool ldquoNeuroinflammationmdashan early event in both the history and pathogenesis ofAlzheimerrsquos diseaserdquo Neurodegenerative Diseases vol 7 no 1ndash3 pp 38ndash41 2010

[39] P Eikelenboom J J M Hoozemans R Veerhuis E Van ExelA J M Rozemuller and W A Van Gool ldquoWhether when andhow chronic inflammation increases the risk of developing late-onset Alzheimerrsquos diseaserdquoAlzheimerrsquos Research ampTherapy vol4 no 3 article no 15 2012

[40] V Afonso R Champy D Mitrovic P Collin and A LomrildquoReactive oxygen species and superoxide dismutases role injoint diseasesrdquo Joint Bone Spine vol 74 no 4 pp 324ndash329 2007

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[42] P Stralin and S L Marklund ldquoMultiple cytokines regulatethe expression of extracellular superoxide dismutase in humanvascular smoothmuscle cellsrdquoAtherosclerosis vol 151 no 2 pp433ndash441 2000

[43] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash384 2005

[44] T Konopka K Krol W Kopec and H Gerber ldquoTotal antioxi-dant status and 8-hydroxy-21015840-deoxyguanosine levels in gingi-val and peripheral blood of periodontitis patientsrdquo ArchivumImmunologiae et Therapiae Experimentalis vol 55 no 6 pp417ndash422 2007

[45] T Yamamoto T Tomofuji N Tamaki D Ekuni T Azuma andT Sanbe ldquoEffects of topical application of lipopolysaccharideand proteases on hepatic injury induced by high-cholesteroldiet in ratsrdquo Journal of Periodontal Research vol 45 no 1 pp129ndash135 2010

[46] F DrsquoAiuto L Nibali M Parkar K Patel J Suvan and NDonos ldquoOxidative stress systemic inflammation and severeperiodontitisrdquo Journal of Dental Research vol 89 no 11 pp1241ndash1246 2010

[47] M Almeida L Han M Martin-Millan C A OrsquoBrien andS C Manolagas ldquoOxidative stress antagonizes Wnt signalingin osteoblast precursors by diverting 120573-catenin from T cellfactor- to forkhead box O-mediated transcriptionrdquoThe Journalof Biological Chemistry vol 282 no 37 pp 27298ndash27305 2007

[48] X-C Bai D Lu J Bai et al ldquoOxidative stress inhibits osteoblas-tic differentiation of bone cells by ERK andNF-120581Brdquo Biochemicaland Biophysical Research Communications vol 314 no 1 pp197ndash207 2004

[49] NMody F Parhami T A Sarafian and L L Demer ldquoOxidativestress modulates osteoblastic differentiation of vascular andbone cellsrdquo Free Radical Biology and Medicine vol 31 no 4 pp509ndash519 2001

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[51] N J Simmonds R E Allen T R J Stevens R N M VanSomeren D R Blake andD S Rampton ldquoChemiluminescenceassay of mucosal reactive oxygen metabolites in inflammatorybowel diseaserdquo Gastroenterology vol 103 no 1 pp 186ndash1961992

[52] M B Grisham R P MacDermott and E A Deitch ldquoOxidantdefensemechanisms in the human colonrdquo Inflammation vol 14no 6 pp 669ndash680 1990

[53] B Sido V Hack A Hochlehnert H Lipps C Herfarth andW Droge ldquoImpairment of intestinal glutathione synthesis inpatients with inflammatory bowel diseaserdquo Gut vol 42 no 4pp 485ndash492 1998

[54] L Lih-Brody S R Powell K P Collier et al ldquoIncreasedoxidative stress and decreased antioxidant defenses in mucosaof inflammatory bowel diseaserdquoDigestive Diseases and Sciencesvol 41 no 10 pp 2078ndash2086 1996

[55] M B Grisham ldquoOxidants and free radicals in inflammatorybowel diseaserdquoTheLancet vol 344 no 8926 pp 859ndash861 1994

[56] V Gross H Arndt T Andus K D Palitzsch and JScholmerich ldquoFree radicals in inflammatory bowel diseasespathophysiology and therapeutic implicationsrdquo Hepatogas-troenterology vol 41 no 4 pp 320ndash327 1994

[57] A Banan S Choudhary Y Zhang J Z Fields and AKeshavarzian ldquoOxidant-induced intestinal barrier disruptionand its prevention by growth factors in a human colonic cellline role of the microtubule cytoskeletonrdquo Free Radical Biologyand Medicine vol 28 no 5 pp 727ndash738 2000

[58] G Bellomo F Mirabelli M Vairetti F Iosi and W MalornildquoCytoskeleton as a target inmenadione-induced oxidative stressin cultured mammalian cells I Biochemical and immunocyto-chemical featuresrdquo Journal of Cellular Physiology vol 143 no 1pp 118ndash128 1990

[59] Y Zhao and B Zhao ldquoOxidative stress and the pathogenesis ofAlzheimerrsquos diseaserdquoOxidativeMedicine andCellular Longevityvol 2013 Article ID 316523 10 pages 2013

[60] M Sochocka E S Koutsouraki K Gasiorowski and J LeszekldquoVascular oxidative stress and mitochondrial failure in thepathobiology of Alzheimerrsquos disease a new approach to ther-apyrdquo CNS and Neurological DisordersmdashDrug Targets vol 12 no6 pp 870ndash881 2013

[61] MA LovellWD Ehmann SM Butler andWRMarkesberyldquoElevated thiobarbituric acid-reactive substances and antiox-idant enzyme activity in the brain in Alzheimerrsquos diseaserdquoNeurology vol 45 no 8 pp 1594ndash1601 1995

[62] M A Lovell W D Ehmann M P Mattson and W RMarkesbery ldquoElevated 4-hydroxynonenal in ventricular fluid inAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 18 no 5 pp457ndash461 1997

[63] W R Markesbery and M A Lovell ldquoFour-hydroxynonenala product of lipid peroxidation is increased in the brain inAlzheimerrsquos diseaserdquoNeurobiology of Aging vol 19 no 1 pp 33ndash36 1998

[64] K S Montine E Reich M D Neely et al ldquoDistributionof reducible 4-hydroxynonenal adduct immunoreactivity inAlzheimer disease is associated with APOE genotyperdquo Journalof Neuropathology amp Experimental Neurology vol 57 no 5 pp415ndash425 1998

[65] L T McGrath B M McGleenon S Brennan D McColl SMcIlroy and A P Passmore ldquoIncreased oxidative stress inAlzheimerrsquos disease as assessed with 4-hydroxynonenal but notmalondialdehyderdquo QJMmdashMonthly Journal of the Association ofPhysicians vol 94 no 9 pp 485ndash490 2001

[66] K Hensley N Hall R Subramaniam et al ldquoBrain regional cor-respondence between Alzheimerrsquos disease histopathology andbiomarkers of protein oxidationrdquo Journal of Neurochemistryvol 65 no 5 pp 2146ndash2156 1995

[67] M Y Aksenov M V Aksenova D A Butterfield J W Geddesand W R Markesbery ldquoProtein oxidation in the brain inAlzheimerrsquos diseaserdquo Neuroscience vol 103 no 2 pp 373ndash3832001

[68] M Violet L Delattre M Tardivel et al ldquoA major role for Tauin neuronal DNA and RNA protection in vivo under phys-iological and hyperthermic conditionsrdquo Frontiers in CellularNeuroscience vol 8 article 84 2014

[69] M A Lovell S P Gabbita and W R Markesbery ldquoIncreasedDNA oxidation and decreased levels of repair products inAlzheimerrsquos disease ventricular CSFrdquo Journal of Neurochemistryvol 72 no 2 pp 771ndash776 1999

[70] M Ramamoorthy P Sykora M Scheibye-Knudsen et alldquoSporadic Alzheimer disease fibroblasts display an oxidativestress phenotyperdquo Free Radical Biology andMedicine vol 53 no6 pp 1371ndash1380 2012

[71] M Morocz J Kalman A Juhasz et al ldquoElevated levels ofoxidative DNA damage in lymphocytes from patients withAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 23 no 1 pp47ndash53 2002

[72] E J Mufson E-Y Chen E J Cochran L A Beckett D ABennett and J H Kordower ldquoEntorhinal cortex120573-amyloid loadin individuals with mild cognitive impairmentrdquo ExperimentalNeurology vol 158 no 2 pp 469ndash490 1999

[73] W RMarkesbery F A Schmitt R J Kryscio D G Davis C DSmith and D R Wekstein ldquoNeuropathologic substrate of mildcognitive impairmentrdquo Archives of Neurology vol 63 no 1 pp38ndash46 2006

[74] J L Price D W McKeel Jr V D Buckles et al ldquoNeu-ropathology of nondemented aging presumptive evidence forpreclinical Alzheimer diseaserdquo Neurobiology of Aging vol 30no 7 pp 1026ndash1036 2009

[75] D A Butterfield H F Poon D St Clair et al ldquoRedoxproteomics identification of oxidatively modified hippocampalproteins in mild cognitive impairment insights into the devel-opment of Alzheimerrsquos diseaserdquoNeurobiology of Disease vol 22no 2 pp 223ndash232 2006

[76] J N Keller F A Schmitt S W Scheff et al ldquoEvidence ofincreased oxidative damage in subjects with mild cognitiveimpairmentrdquo Neurology vol 64 no 7 pp 1152ndash1156 2005

[77] P Rinaldi M C Polidori A Metastasio et al ldquoPlasma antiox-idants are similarly depleted in mild cognitive impairment andin Alzheimerrsquos diseaserdquoNeurobiology of Aging vol 24 no 7 pp915ndash919 2003

[78] L L Torres N B Quaglio G T De Souza et al ldquoPeripheraloxidative stress biomarkers in mild cognitive impairment andAlzheimerrsquos diseaserdquo Journal of Alzheimerrsquos Disease vol 26 no1 pp 59ndash68 2011

[79] U Puntener S G Booth V H Perry and J L Teeling ldquoLong-term impact of systemic bacterial infection on the cerebralvasculature and microgliardquo Journal of Neuroinflammation vol9 article 146 2012

[80] Z Wu J Zhang and H Nakanishi ldquoLeptomeningeal cellsactivate microglia and astrocytes to induce IL-10 production byreleasing pro-inflammatory cytokines during systemic inflam-mationrdquo Journal of Neuroimmunology vol 167 no 1-2 pp 90ndash98 2005


[81] Z Wu Y Hayashi J Zhang and H Nakanishi ldquoInvolve-ment of prostaglandin E

2released from leptomeningeal cells

in increased expression of transforming growth factor-120573 inglial cells and cortical neurons during systemic inflammationrdquoJournal of Neuroscience Research vol 85 no 1 pp 184ndash192 2007

[82] Z Wu L Sun S Hashioka et al ldquoDifferential pathways forinterleukin-1120573 production activated by chromogranin A andamyloid 120573 in microgliardquo Neurobiology of Aging vol 34 no 12pp 2715ndash2725 2013

[83] Z Wu Y Tokuda X-W Zhang and H Nakanishi ldquoAge-dependent responses of glial cells and leptomeninges duringsystemic inflammationrdquo Neurobiology of Disease vol 32 no 3pp 543ndash551 2008

[84] X Liu Z Wu Y Hayashi and H Nakanishi ldquoAge-dependentneuroinflammatory responses and deficits in long-term poten-tiation in the hippocampus during systemic inflammationrdquoNeuroscience vol 216 pp 133ndash142 2012

[85] A Gerhard B Neumaier E Elitok et al ldquoIn vivo imaging ofactivated microglia using [11C]PK11195 and positron emissiontomography in patients after ischemic strokerdquoNeuroReport vol11 no 13 pp 2957ndash2960 2000

[86] C J S Price D Wang D K Menon et al ldquoIntrinsic activatedmicroglia map to the peri-infarct zone in the subacute phase ofischemic strokerdquo Stroke vol 37 no 7 pp 1749ndash1753 2006

[87] L Ruan Z Kang G Pei and Y Le ldquoAmyloid deposition andinflammation in APPswePS1dE9 mouse model of Alzheimerrsquosdiseaserdquo Current Alzheimer Research vol 6 no 6 pp 531ndash5402009

[88] E Perry and M-J R Howes ldquoMedicinal plants and dementiatherapy herbal hopes for brain agingrdquo CNS Neuroscience ampTherapeutics vol 17 no 6 pp 683ndash698 2011

[89] V S Bankova S L de Castro and M C Marcucci ldquoPropolisrecent advances in chemistry and plant originrdquo Apidologie vol31 no 1 pp 3ndash15 2000

[90] M C Marcucci ldquoPropolis chemical composition biologicalproperties and therapeutic activityrdquo Apidologie vol 26 no 2pp 83ndash99 1995

[91] G A Burdock ldquoReview of the biological properties and toxicityof bee propolis (propolis)rdquo Food and Chemical Toxicology vol36 no 4 pp 347ndash363 1998

[92] A H Banskota Y Tezuka and S Kadota ldquoRecent progress inpharmacological research of propolisrdquo Phytotherapy Researchvol 15 no 7 pp 561ndash571 2001

[93] J M Sforcin ldquoPropolis and the immune system a reviewrdquoJournal of Ethnopharmacology vol 113 no 1 pp 1ndash14 2007

[94] A F N Ramos and J L Miranda ldquoPropolis a review of itsanti-inflammatory and healing actionsrdquo Journal of VenomousAnimals and Toxins including Tropical Diseases vol 13 no 4pp 697ndash710 2007

[95] E W Englander Z Hu A Sharma H-M Lee Z-H Wu andG H Greeley ldquoRat MYH a glycosylase for repair of oxidativelydamaged DNA has brain-specific isoforms that localize toneuronal mitochondriardquo Journal of Neurochemistry vol 83 no6 pp 1471ndash1480 2002

[96] J M Sforcin and V Bankova ldquoPropolis is there a potential forthe development of new drugsrdquo The Journal of Ethnopharma-cology vol 133 no 2 pp 253ndash260 2011

[97] A Q Zhu C L Masters and Q X Li ldquoTibet-medicineratanasampil modulates amyloid precursor protein cleavageand C-terminal fragments (CTFS) in Tg2576 transgenic micebrain of Alzheimerrsquos diseaserdquo Chinese Journal of GeriatricDentistry vol 11 pp 950ndash954 2009

[98] A Q Zhu Q Xia G F Li et al ldquoRatanasampil (tibetanmedicine RNSP) reduces A-amyloid protein and pro-inflammatory factor levels and improves cognitive functions inmild-to-moderate Alzheimerrsquos disease (AD) patients living athigh altituderdquo Journal of Behavioral and Brain Science vol 2pp 82ndash91 2012

[99] Y Liu Z Wu X Zhang et al ldquoLeptomeningeal cells transduceperipheral macrophages inflammatory signal to microglia inreponse to Porphyromonas gingivalis LPSrdquoMediators of Inflam-mation vol 2013 Article ID 407562 11 pages 2013

[100] H Sies W Stahl and A Sevanian ldquoNutritional dietary andpostprandial oxidative stressrdquo Journal of Nutrition vol 135 no5 pp 96ndash972 2005

[101] H Sies ldquoOxidative stress a concept in redox biology andmedicinerdquo Redox Biology vol 4 pp 180ndash183 2015

[102] PMecocci UMacGarvey andM F Beal ldquoOxidative damage tomitochondrial DNA is increased inAlzheimerrsquos diseaserdquoAnnalsof Neurology vol 36 no 5 pp 747ndash751 1994


[104] P Mecocci E Mariani V Cornacchiola and M C PolidorildquoAntioxidants for the treatment of mild cognitive impairmentrdquoNeurological Research vol 26 no 5 pp 598ndash602 2004

[105] C Lefebvre drsquoHellencourt C N Montero-Menei R BernardandD Couez ldquoVitaminD3 inhibits proinflammatory cytokinesand nitric oxide production by the EOC13 microglial cell linerdquoJournal of Neuroscience Research vol 71 no 4 pp 575ndash5822003

[106] Y Li L Liu S W Barger R E Mrak and W S T GriffinldquoVitamin E suppression of microglial activation is neuroprotec-tiverdquo Journal ofNeuroscience Research vol 66 no 2 pp 163ndash1702001

[107] J P Godbout B M Berg K W Kelley and R W Johnson ldquo120572-tocopherol reduces lipopolysaccharide-induced peroxide rad-ical formation and interleukin-6 secretion in primary murinemicroglia and in brainrdquo Journal of Neuroimmunology vol 149no 1-2 pp 101ndash109 2004

[108] L A Bialowas-McGoey A Lesicka and P M Whitaker-Azmitia ldquoVitamin E increases S100b-mediated microglial acti-vation in an S100b-overexpressingmousemodel of pathologicalagingrdquo Glia vol 56 no 16 pp 1780ndash1790 2008

[109] MDjukicM L Onken S Schutze et al ldquoVitaminD deficiencyreduces the immune response phagocytosis rate and intracel-lular killing rate ofmicroglial cellsrdquo Infection and Immunity vol82 no 6 pp 2585ndash2594 2014

[110] E Hjorth M Zhu V C Toro et al ldquoOmega-3 fatty acidsenhance phagocytosis of alzheimerrsquos disease-related amyloid-12057342 by human microglia and decrease inflammatory markersrdquoJournal of Alzheimerrsquos Disease vol 35 no 4 pp 697ndash713 2013

[111] S Chen H Zhang H Pu et al ldquon-3 PUFA supplementationbenefits microglial responses to myelin pathologyrdquo ScientificReports vol 4 article 7458 2014

[112] R M Ortega A M Requejo A M Lopez-Sobaler et alldquoCognitive function in elderly people is influenced by vitaminE statusrdquoThe Journal of Nutrition vol 132 no 7 pp 2065ndash20682002

[113] K Murakami N Murata Y Ozawa et al ldquoVitamin C restoresbehavioral deficits and amyloid-120573 oligomerization withoutaffecting plaque formation in a mouse model of alzheimerrsquos


diseaserdquo Journal of Alzheimerrsquos Disease vol 26 no 1 pp 7ndash182011

[114] L An and T Zhang ldquoVitamins C and E reverse melamine-induced deficits in spatial cognition and hippocampal synapticplasticity in ratsrdquo Neurotoxicology vol 44 pp 132ndash139 2014

[115] M G Isaac R Quinn andN Tabet ldquoVitamin E for Alzheimerrsquosdisease and mild cognitive impairmentrdquo Cochrane DatabaseSystematic Reviews vol 16 no 3 Article ID CD002854 2008

[116] J C Agnew-Blais S Wassertheil-Smoller J H Kang et alldquoFolate vitaminB-6 and vitaminB-12 intake andmild cognitiveimpairment and probable dementia in the Womenrsquos HealthInitiative Memory studyrdquo Journal of the Academy of Nutritionand Dietetics vol 115 no 2 pp 231ndash241 2015

[117] A M Alavi Naeini I Elmadfa A Djazayery et al ldquoThe effectof antioxidant vitamins E and C on cognitive performance ofthe elderly with mild cognitive impairment in Isfahan Iran adouble-blind randomized placebo-controlled trialrdquo EuropeanJournal of Nutrition vol 53 no 5 pp 1255ndash1262 2014

[118] E S Abd Allah A M Gomaa and M M Sayed ldquoThe effectof omega-3 on cognition in hypothyroid adult male ratsrdquo ActaPhysiologica Hungarica vol 101 no 3 pp 362ndash376 2014

[119] T Cederholm N Salem Jr and J Palmblad ldquo120596-3 Fatty acidsin the prevention of cognitive decline in humansrdquo Advances inNutrition vol 4 no 6 pp 672ndash676 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


have found that RNSP a traditional Tibetan medicine whichis composed of 70 herbal components improves the cognitivefunction in middle-to-moderate AD patients living at highaltitude by reducing the levels of proinflammatory mediatorsand the deposition of A120573 [21] In the present review we willhighlight our proposed concept of microglia aging whichrefers to the fact that microglia are the potent acceleratorsof brain aging due to their induction of cognitive declineWe will also discuss the benefits of nutrients in preventingmicroglia aging and cognitive decline

2 The Risk of Systemic InflammatoryDiseases for AD

RA is a chronic inflammatory bone disorder which causesjoint damage A postmortem survey found that the preva-lence of AD was reduced in RA patients who were long-term users of nonsteroidal anti-inflammatory agents [22ndash25]More recently patients with midlife RA were confirmed tohave an increased risk of cognitive impairment over a 21-year follow-up study in several case-control andhospital- andregister-based studies that were performed to examine theassociation between RAarthritis and dementiaAD [26]

Periodontitis is a chronic inflammatory disorder in theperiodontal tissuesThere is growing clinical evidence to sup-port a close link between periodontitis and the developmentand progression of AD [27 28] More recently the threemajor periodontal bacteria ldquoRed complexrdquo including Tre-ponema denticola Tannerella forsythia and Porphyromonasgingivalis and their components have been detected in thebrain of AD patients [29 30] More details have beenreviewed by us recently [20]

IBD is a chronic inflammatory disorder in the gutThe gutbacteria are important for inducing systemic inflammationand LPS is a potentially associated mediator which migratesinto the intestinal capillaries [31] Indeed elevated LPSconcentrations can be found in the plasma of AD patients[32ndash34] which supports a possible role of LPS in the pro-motion of neuroinflammation and the triggering cognitivedecline [35ndash37] Furthermore the chronically inflamed gutgenerates systemic proinflammatory cytokines to promoteneuroinflammation which causes cognitive decline [38 39]

3 Oxidative Damage in SystemicInflammatory Diseases and AD

31 Oxidative Damage in the Chronic Inflammatory DisordersROS contribute to the progression of chronic inflammatorybone disorders including RA and periodontitis The inflam-matory cell-mediated overproduction of TNF-120572 is thought tobe the main contributor to the increased release of ROS inRA patients [40] because TNF-120572 not only causes cell damagebut also inhibits antioxidants such as superoxide dismutase 1(SOD1) and SOD3 [41 42] Numerous studies have indicatedexcess ROS levels and the depletion of antioxidant levelsin the gingival crevicular fluid [43 44] There is furtherevidence of higher levels of lipid peroxidation hydrogenperoxides and oxidative DNA damage in animal models of

periodontitis [45] Indeed periodontitis is associated withsystemic oxidative stress and a reduced global antioxidantcapacity which suggests that oxidative stress in patientswith periodontitis could be closely linked to the biomarkerof inflammation including C-reactive protein [46] It isconsidered that ROS are involved in the chronic inflam-matory bone disorders by regulating osteoblasts and osteo-clasts [47] because the increasedmitochondria-derived ROSespecially H

2O2 reduces the differentiation and maturation

of osteoblasts by inhibiting type 1 collagen and alkalinephosphatase colony-forming unit-osteoprogenitor forma-tion and Runt-related transcription factor 2 activation [4849] On the other hand the increased ROS enhance theosteoclast numbers and resorption by stimulating receptoractivator of NF-120581B ligand and TNF-120572 expression throughextracellular-signal-regulated kinase and NF-120581B activation[50]

ROS are increased in the colonic mucosa of patientswith the alterations in the mucosal antioxidant defenses inIBD patients [51 52] because the bodyrsquos major antioxidantglutathione is depleted but its oxidized form glutathionedisulfide is increased in individuals with active IBD [53 54]The imbalance caused by the increase of ROS productionand the decrease of antioxidant capacity-induced oxidativestress is considered to be themajor pathogenic mechanism ofIBD [55 56] Excessive levels of ROS result in damage to thecytoskeleton protein including the temporal disruption ofthe barrier integrity and increasing gut permeability [57 58]Therefore ROS promote oxidative damage modulate theintra- and extracellular redox status and interfere with theactivation of proteolytic enzymes in the systemic inflamma-tory environment

32 Oxidative Damage in AD Oxidative stress is consideredto be the main cause of AD In microglia mitochondrialdysfunction leads to the excess production of ROS whichpromotes the redox imbalance and stimulates proinflamma-tory gene transcription and the release of cytokines suchas IL-1 IL-6 and TNF-120572 thereby inducing neuroinflam-mation The neuroinflammation-prolonged oxidative stressleads to the accumulation of A120573 and tau phosphorylationand then induces neurotoxicity in AD patients [59 60]Thus microglia-mediated neuroinflammation is perceived asa cause and a consequence of chronic oxidative stress

Extensive oxidative stress is observed in all of the cellularmacromolecules of AD patients First lipid peroxidationis greatly enhanced in AD The 4-hydroxynonal levels aresignificantly elevated in the hippocampus entorhinal cor-tex temporal cortex amygdala parahippocampal gyrus andventricular fluid [61ndash64] and plasma [65] of AD patientsSecond the oxidative modification of proteins which resultsfrom either a direct ROS attack or from the reactions thatoccur through the binding of glycation glycoxidation andlipid peroxidation products has been extensively shown inADThemost widely studiedmarkers of protein oxidation areprotein carbonyls and 3-nitrotyrosine Significant increases ofprotein carbonyl are observed in the hippocampus parietallobe and superior middle temporal gyrus of AD patients[66 67] Third oxidative damage occurs in the DNARNA















Young Middle Aged


Microglia aging


Cognitive decline

ROS


ROS


Slow brain aging





2D3







6 Conclusion






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























Young Middle Aged


Microglia aging


Cognitive decline

ROS


ROS


Slow brain aging





2D3







6 Conclusion






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Young Middle Aged


Microglia aging


Cognitive decline

ROS


ROS


Slow brain aging





2D3







6 Conclusion






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















6 Conclusion






Acknowledgment


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Nutrients, Microglia Aging, and Brain Aging