Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. It is characterized by the presence of two aberrant structures within the patient’s brain, namely senile plaques and neurofibrillary tangles (NFTs). In addition, it causes the loss of neuronal function and neuronal death in the later stages of the disease (1).
The main component of senile plaques and NFTs are amyloid beta (Aβ) peptide and tau proteins (2), respectively. Aβ is cleaved from the larger amyloid precursor protein (APP) (3). In the familial type of AD (FAD), which has an incidence below 5%, mutations in APP and in presenilin 1 and 2 genes can lead to increased levels of Aβ, which may be related to the onset of the disease (4). For the remaining cases of (sporadic) AD, which typically develops later than familial AD, the cause is largely unknown. Given that the degenerative process of the two forms of the disease are similar, it is thought that they share the same underlying mechanism.
On the basis of these observations, Aβ has become a major pharmacological target for the treatment of the disease. The amyloid cascade-inflammatory hypothesis has been put forward to explain the mechanism underlying Aβ toxicity in AD (5), (6), (7), (8), (9), (10), (11). This hypothesis proposes that Aβ induces an inflammatory response that is enhanced by the presence of tau. An excess of soluble Aβ species, as well as aggregated Aβ and hyperphosphorylated tau proteins, interferes with neuronal function and triggers the inflammatory activity of microglia, some of the primary events being those that initiate AD pathology. It has even been discussed whether a pro-inflammatory process could precede AD (12), (13). The inflammatory response is driven mainly by activated microglia (14). The activation of these cells has been reported in both AD patients and animal models of this disease (15), and it is accompanied by increased levels of specific chemokines and cytokines (16). In addition, the protective effects of non-steroidal anti-inflammatory drugs (NSAIDs) against AD development (17) further support the neuroinflammation hypothesis of AD (5). Finally, as the disease progresses, neurodegeneration ensues, interfering with the properties of the central nervous system (CNS) and thus affecting neuronal function, as well as the structure and survival of the neurons themselves.
Microglia are glial cells located in the CNS. They play a macrophage-like role in the immune defense of this system (18), (19), (20), (21). These cells were named by the Spanish neuroscientist Pío del Río Hortega about a century ago (22), (23). He postulated that microglia serve as macrophages by phagocytosing toxic elements in the CNS.
The origin of microglia differs from that of other types of brain glia or macroglia. In the mouse brain, microglia originate from myeloid progenitors in the yolk sac that migrate into the brain during early embryonic stages, before the blood-brain barrier is formed (24). Under physiological conditions, microglia proliferate throughout embryogenesis and self-renew constantly throughout life to maintain cell numbers, without a contribution from bone marrow-derived macrophages (25).
Recent evidence shows that microglia are highly dynamic. Under both physiological and pathological conditions, they monitor their environment and regulate tissue homeostasis through scavenging functions (26). Therefore, resident microglia have functions related to immune surveillance (27); adult neurogenesis and refinement of synaptic networks such as synapse pruning, promotion or removal apoptosis, secretion of growth factors, among others (28). During the regulation of brain homeostasis, microglia can undergo changes in their metabolism and morphology (24), (29). In this regard, two main microglia types, namely resting and activated, have been described (Figure 1A–D). The former show long cytoplasmic extensions that are in continuous movement. The latter change shape to become an activated and mobile amoeboid, which can be recognized by the expression of ionized calcium binding adapter molecule 1 (Iba1) or cluster of differentiation (CD) 68 (CD68) markers. The transition of a microglial cell from the resting to the activated type and the resulting changes in morphology are promoted by various extracellular cytokines or factors such as lipids or lipopolysaccharides (LPS) (30), (31). Also, a transition to senescent glia could take place in some pathologies like AD (13).
Activated microglia, like peripheral macrophages, are often classified into inflammatory (M1) and alternatively activated (M2) phenotypes (32) (Figure 1A). However, these cells show high levels of diversity and plasticity and their classification into an M1 or M2 polarized state may be an oversimplification (14), (33), (34). Recently, it has been proposed that microglia switch continuously between phenotypes (35), (36). However, the M1 phenotype is induced by means of interferon (IFN)-γ and LPS stimulation, among others, and the M2 phenotype by means of interleukin (IL)-4, IL-10, and IL-13 (31), (37), etc. (Figure 1B). M1 microglia are associated with the production and release of pro-inflammatory cytokines, namely tumor necrosis factor (TNF)-α, IL-6, IL-23, IL-1β, IL-12, nitric oxide (NO), and chemokines, among others (38) (Figure 1C). In contrast, M2 microglia express anti-inflammatory molecules, such as IL-10 and transforming growth factor (TGF)-β, and extracellular matrix molecules (39). In addition, it has been proposed that M1 microglia predominate at the site of injury under pathological situations, whereas M2 microglia appear later at a stage more related to repair processes (34). In most cases, microglia in AD patients exhibit mixed activation phenotypes. Indeed, cortical tissue from the Tg2576 mouse and individuals with AD show a mixed profile of alternative activation and classical activation genes (40).
Neurodegenerative diseases are associated with elderly people. In this regard, it has also been hypothesized that aging leads to the dysfunction or dystrophia of these cells (34). Nevertheless, a larger reduction in process length and arborized area in AD compared to aged-matched control microglia has recently been described (41).
Activation of microglia
Bacterial LPS is the major outer surface membrane component present in almost all Gram-negative bacteria, and it is an extremely strong stimulator of innate or natural immunity. LPS can bind to microglia to induce the M1 phenotype, which secretes pro-inflammatory cytokines (31) that promote the inflammatory response. The secretion of these molecules can be prevented by anti-inflammatory therapeutic agents, specifically by NSAIDs (42) (Figure 1A). NSAIDs exert their effects by inhibiting the activity of cyclooxygenase (COX) enzymes COX1 and COX2 (43). Ibuprofen is a NSAID and therefore has the capacity to inhibit COX1 and COX2. In this regard, the potential of ibuprofen to inhibit the effects of LPS in mouse models has been addressed (44). COX1 is expressed mainly in microglial cells and COX2 in neurons (45). COX protein expression has not been reported in astrocytes (46). However, the inhibition of COX1 does not totally block the inflammatory response.
This observation suggests that NSAIDs could initiate other elements involved in the inflammatory response. One such element is the multi-protein complex known as the inflammasome (47), (48), (49). Inflammasomes have been linked to a variety of auto-inflammatory and auto-immune diseases, including neurodegenerative diseases and metabolic disorders (50). Therefore, the inflammatory cytokine IL-1β secreted by activated microglia is synthesized as an inactive precursor and it requires the action of caspase 1 to become active (51). Increased amounts of cleaved caspase-1 have been reported in hippocampal and cortical lysates from AD patients compared to controls. This finding is consistent with chronic inflammasome activation (47). The best characterized inﬂammasome-forming pattern recognition receptor and the one most commonly associated with AD is NLRP3 (NLR family, pyrin-domain containing 3) (47). Previous activation of caspase-1 requires the NLRP3 inflammasome (52). The NLRP3/caspase-1 axis plays an important role in AD pathogenesis, and therefore inhibition of the NLRP3 inflammasome emerges as a novel therapeutic intervention for neurological diseases that course with inflammation.
Role of Aβ in brain inflammation
In animal models overexpressing Aβ, inflammatory responses to amyloidosis could take place (53), (54). In this amyloidosis microglia could exert neuroprotective activity by degrading Aβ (55). In AD, these cells have a reduced capacity for Aβ clearance, which results in additional accumulation of this peptide (56). Microglia-mediated clearance of Aβ occurs through the TLR4, the same receptor that is used for LPS action (57). Thus, Aβ (mainly in an aggregated form) is a TLR4 ligand, and chronic exposure of this receptor to Aβ can result in TLR signaling dysfunction and inflammation (57), (58). Aβ aggregates interact with other microglial receptors like CD14, CD36, CD47, the receptor for advanced glycation end products (RAGE), and some integrins (59), (60), (61), (62). It has been proposed that the binding of Aβ to CD36 regulates inflammasome activation (63). In addition, Aβ peptide may activate the NLRP3 inflammasome in microglia (64). More recently, it has been reported that Aβ activates microglia through its interaction with the APP present in the membrane of these cells (65). This finding defines a novel function of APP in microglial regulation of the inflammatory response in AD (65).
Role of tau in brain inflammation
Tau is a neuronal microtubule-associated protein whose main function is to stabilize microtubules (66). The pathological aggregations of hyperphosphorylated tau are the defining histopathological features of AD and other tauopathies. Recent research has shown that NFTs themselves are not the most toxic form of tau, but rather the smaller aggregates, called tau oligomers, which are likely to initiate neurodegeneration in tauopathies. Oligomeric tau can be released into the extracellular space and can spread throughout the brain. Activated microglia are frequently present in the proximity of NFTs in the hippocampus of AD patients, thereby indicating a close relationship between the inflammatory response and tau neurofibrillary lesions. Furthermore, tau can be phagocytosed by microglia (67). This finding would support the notion that impaired clearance of extracellular tau (by microglia) contributes to the spread of pathological tau, as shown in AD (68).
In animal models of tauopathies, tau dysfunction may result in changes in neuroinflammatory gene regulation (69). Deficits in tau function affect various neuronal functions, such as the secretion of proteins like fractalkine (CX3CL1) (70), (71). CX3CL1 secreted by neurons can bind to its receptor in microglia (CX3CR1), and this process maintains microglia in an ‘off’ state (72), thereby inhibiting the release of inflammatory cytokines (73), (74). The deficiency of CX3CR1 in microglia results in increased secretion of IL-1β. This pro-inflammatory cytokine interacts with neurons, thereby enhancing tau neuronal pathology via p38MAPK (75).
A main tau modification, occurring in AD, is its phosphorylation. Tau hyperphosphorylation could be toxic, independently if it forms toxic aggregates or could remain in soluble form (76). In this way, tau toxicity could result in an inflammatory process that could be prevented by the inhibition of tau kinases, like GSK3 (77). However, tau phosphorylation at different residues could result in different toxicity levels and even a site-specific phosphorylation of tau could inhibit amyloid toxicity, in a mouse model (78).
Other factors modulate inflammation
In recent years, genome-wide association studies (GWAS) have identified a large number of risk genes for AD. In this regard, the R47H mutation in Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported as a risk for this disease. TREM2 is a transmembrane glycoprotein that is expressed exclusively by immune cells in the brain. Mutations in TREM2 are associated with microglial dystrophy, decreased phagocytosis, and an increased pro-inflammatory reactive phenotype. These features increase the risk of AD, as previously described (79), (80). It has been shown that TREM2 deﬁciency increases LPS-induced IL-6 and IL-1β mRNA levels in microglia. This observation thus indicates that TREM2 restrains microglia activation (81).
Environmental factors contribute to the regulation of microglia. An example of this is the communication from gut to brain (29), (30), (82). The human intestine contains many microbial cells that secrete factors, which, after crossing the blood-brain barrier, reach the CNS to interact with microglia. In this way, microbiota could have the capacity to modulate behavioral and physiological abnormalities associated with neuronal disorders (30).
Allergic diseases are generally accompanied by chronic systemic inflammation. The effects of allergy on AD have not been addressed, but epidemiological studies suggest that the presence of allergic diseases, especially asthma, is associated with an almost two-fold increase in the risk of developing any form of dementia, including AD, later in life (83), (84). Asthma is an inflammatory disease of the airways, and it is characterized by airway eosinophilia, in which the CCL11 (eotaxin-1) chemokine plays a crucial role. Eotaxin-1 is a key molecule in eosinophil chemoattraction and activation in asthma pathogenesis (85). Of note, eotaxin-1 levels increase throughout life, thus being a molecular effector of aging, the largest risk factor for developing AD (86). It has been shown that plasma eotaxin-1 levels are correlated with AD patients. Therefore, low to moderate eotaxin-1 levels elicit a normal or protective response, while higher levels ultimately lead to neurodegeneration and memory impairment (87).
Studies in mice revealed an association between allergy and increased phosphorylation of tau (88). More recently, it has been described that allergic long-term inflammation results in a reduction in the number of activated microglia at the dentate gyrus, together with enhanced neurogenesis in that brain region (89).
Taken together, all these observations support the notion that cross-talk between peripheral tissues and the CNS could regulate microglial activation, and, in some cases, might result in the onset of neurodegeneration.
Neuroinflammation is one of the main triggers of neurodegeneration. Research into the factors and pathways able to induce the first steps of the inflammatory response would lead to the identification of potential therapeutic targets through which to halt the progression of AD.
List of abbreviations
beta amyloid peptide
amyloid precursor protein
non-steroidal anti-inflammatory drugs
cluster of differentiation
tumor necrosis factor α
transforming growth factor β
receptor for advanced glycation end products
genome-wide association study
triffering receptor expressed in myeloid cells 2
Alzheimer A. Über eine eigenartige Erkankung der Hirnrinde. Psych genchtl Med 1907; 64: 146–8. Google Scholar
Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer’s disease. Lancet 2016; 388: 505–17. Google Scholar
Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 1987; 235: 877–80. Google Scholar
McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 2013; 126: 479–97. Google Scholar
Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 2015; 16: 358–72. Google Scholar
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21: 383–421. Google Scholar
Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer’s disease. Arch Pharm Res 2010; 33: 1539–56. Google Scholar
Holmes C. Review: systemic inflammation and Alzheimer’s disease. Neuropathol Appl Neurobiol 2013; 39: 51–68. Google Scholar
Perry VH. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol 2010; 120: 277–86. Google Scholar
Sardi F, Fassina L, Venturini L, Inguscio M, Guerriero F, Rolfo E, Ricevuti G. Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev 2011; 11: 149–53. Google Scholar
Ferretti MT, Cuello AC. Does a pro-inflammatory process precede Alzheimer’s disease and mild cognitive impairment? Curr Alzheimer Res 2011; 8: 164–74. Google Scholar
Streit WJ, Braak H, Xue QS, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 2009; 118: 475–85. Google Scholar
Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 2016; 353: 777–83. Google Scholar
Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB. In vivo measurement of activated microglia in dementia. Lancet 2001; 358: 461–7. Google Scholar
Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 2010; 68: 930–41. Google Scholar
Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008; 70: 1672–7. Google Scholar
Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014; 6: 13. Google Scholar
Streit WJ. Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Brain Res Rev 2005; 48: 234–9. Google Scholar
Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol 2010; 119: 89–105. Google Scholar
Graeber MB, Li W, Rodriguez ML. Role of microglia in CNS inflammation. FEBS Lett 2011; 585: 3798–805. Google Scholar
Tremblay ME, Lecours C, Samson L, Sanchez-Zafra V, Sierra A. From the Cajal alumni Achucarro and Rio-Hortega to the rediscovery of never-resting microglia. Front Neuroanat 2015; 9: 45. Google Scholar
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 2011; 91: 461–553. Google Scholar
Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci 2013; 7: 45. Google Scholar
Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 2014; 82: 380–97. Google Scholar
Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest 2012; 122: 1164–71. Google Scholar
Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada González F, Perrin P, Keren-Shaul H, Gury M, Lara-Astaiso D, Thaiss CA, Cohen M, Bahar Halpern K, Baruch K, Deczkowska A, Lorenzo-Vivas E, Itzkovitz S, Elinav E, Sieweke MH, Schwartz M, Amit I. Microglia development follows a stepwise program to regulate brain homeostasis. Science 2016; 353: aad8670. Google Scholar
Ransohoff RM, El Khoury J. Microglia in Health and Disease. Cold Spring Harb Perspect Biol 2016; 8: a020560. Google Scholar
Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermöhlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015; 18: 965–77. Google Scholar
Mosher KI, Wyss-Coray T. Go with your gut: microbiota meet microglia. Nat Neurosci 2015; 18: 930–1. Google Scholar
Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 2016; 173: 649–65. Google Scholar
Boche D, Perry VH, Nicoll JA. Activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 2013; 39: 3–18. Google Scholar
Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 2016; 19: 987–91. Google Scholar
Tang Y, Le W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol 2016; 53: 1181–94. Google Scholar
Town T, Nikolic V, Tan J. The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflamm. 2005; 2: 24. Google Scholar
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015; 14: 388–405. Google Scholar
Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013; 16: 1211–8. Google Scholar
Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics 2010; 7: 366–77. Google Scholar
Michell-Robinson MA, Touil H, Healy LM, Owen DR, Durafourt BA, Bar-Or A, Antel JP, Moore CS. Roles of microglia in brain development, tissue maintenance and repair. Brain 2015; 138(Pt 5): 1138–59. Google Scholar
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflamm 2006; 3: 27. Google Scholar
Davies DS, Ma J, Jegathees T, Goldsbury AC. Microglia show altered morphology and reduced arborisation in human brain during aging and Alzheimer’s disease. Brain Pathol 2016. Google Scholar
Llorens-Martin M, Jurado-Arjona J, Bolos M, Pallas-Bazarra N, Avila J. Forced swimming sabotages the morphological and synaptic maturation of newborn granule neurons and triggers a unique pro-inflammatory milieu in the hippocampus. Brain Behav Immun 2016; 53: 242–54. Google Scholar
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231: 232–5. Google Scholar
Morihara T, Teter B, Yang F, Lim GP, Boudinot S, Boudinot FD, Frautschy SA, Cole GM. Ibuprofen suppresses interleukin-1beta induction of pro-amyloidogenic alpha1-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer’s models. Neuropsychopharmacology 2005; 30: 1111–20. Google Scholar
Deininger MH, Schluesener HJ. Cyclooxygenases-1 and -2 are differentially localized to microglia and endothelium in rat EAE and glioma. J Neuroimmunol. 1999; 95(1–2): 202–8. Google Scholar
Hoozemans JJ, Rozemuller AJ, Janssen I, De Groot CJ, Veerhuis R, Eikelenboom P. Cyclooxygenase expression in microglia and neurons in Alzheimer’s disease and control brain. Acta Neuropathol 2001; 101: 2–8. Google Scholar
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng T-C, Gelpi E, Halle A, Korte M, Latz E, Golenbock D. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493: 674–8. Google Scholar
Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci 2014; 15: 84–97. Google Scholar
Pan Y, Chen XY, Zhang QY, Kong LD. Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun 2014; 41: 90–100. Google Scholar
Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature 2012; 481: 278–86. Google Scholar
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015; 21: 677–87. Google Scholar
Daniels MJ, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, Booth SJ, White CS, Baldwin AG, Freeman S, Wong R, Latta C, Yu S, Jackson J, Fischer N, Koziel V, Pillot T, Bagnall J, Allan SM, Paszek P, Galea J, Harte MK, Eder C, Lawrence CB, Brough D. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun 2016; 7: 12504. Google Scholar
Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, Olschowka JA, Fonseca MI, O’Banion MK, Tenner AJ, Lemere CA, Duff K. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 2001; 158: 1345–54. Google Scholar
Wirz KT, Bossers K, Stargardt A, Kamphuis W, Swaab DF, Hol EM, Verhaagen J. Cortical β- amyloid protein triggers an immune response, but no synaptic changes in the APPswe/PS1dE9 Alzheimer’s disease mouse model. Neurobiol Aging 2013; 34: 1328–42. Google Scholar
Takata K, Kitamura Y, Saeki M, Terada M, Kagitani S, Kitamura R, Fujikawa Y, Maelicke A, Tomimoto H, Taniguchi T, Shimohama S. Galantamine-induced amyloid-β clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem 2010; 285: 40180–91. Google Scholar
Lee CY, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna) 2010; 117: 949–60. Google Scholar
Go M, Kou J, Lim JE, Yang J, Fukuchi KI. Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer’s mouse model: Implication of TLR4 signaling in disease progression. Biochem Biophys Res Commun 2016; 479: 331–7. Google Scholar
Hines DJ, Choi HB, Hines RM, Phillips AG, MacVicar BA. Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides. PLoS One 2013; 8: e60388. Google Scholar
Du Yan S, Zhu H, Fu J, Yan SF, Roher A, Tourtellotte WW, Rajavashisth T, Chen X, Godman GC, Stern D, Schmidt AM. Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci USA 1997; 94: 5296–301. Google Scholar
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11: 155–61. Google Scholar
Koenigsknecht J, Landreth G. Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism. J Neurosci 2004; 24: 9838–46. Google Scholar
Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K. The LPS receptor (CD14) links innate immunity with Alzheimer’s disease. FASEB J 2004; 18: 203–5. Google Scholar
Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, Moore KJ. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 2013; 14: 812–20. Google Scholar
Gold M, El Khoury J. β-Amyloid, microglia, and the inflammasome in Alzheimer’s disease. Semin Immunopathol 2015; 37: 607–11. Google Scholar
Manocha GD, Floden AM, Rausch K, Kulas JA, McGregor BA, Rojanathammanee L, Puig KR, Puig KL, Karki S, Nichols MR, Darland DC, Porter JE, Combs CK. APP regulates microglial phenotype in a mouse model of Alzheimer’s Disease. J Neurosci 2016; 36: 8471–86. Google Scholar
Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004; 84: 361–84. Google Scholar
Bolos M, Llorens-Martin M, Jurado-Arjona J, Hernandez F, Rabano A, Avila J. Direct evidence of internalization of tau by microglia in vitro and in vivo. J Alzheimers Dis 2015; 50: 77–87. Google Scholar
Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 2015; 138(Pt 6): 1738–55. Google Scholar
Lopez-Gonzalez I, Aso E, Carmona M, Armand-Ugon M, Blanco R, Naudi A, Cabré R, Portero-Otin M, Pamplona R, Ferrer I. Neuroinflammatory gene regulation, mitochondrial function, oxidative stress, and brain lipid modifications with disease progression in tau P301S transgenic mice as a model of frontotemporal lobar degeneration-tau. J Neuropathol Exp Neurol 2015; 74: 975–99. Google Scholar
Chen P, Zhao W, Guo Y, Xu J, Yin M. CX3CL1/CX3CR1 in Alzheimer’s disease: a target for neuroprotection. Biomed Res Int 2016; 2016: 8090918. Google Scholar
Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010; 68: 19–31. Google Scholar
Biber K, Neumann H, Inoue K, Boddeke HW. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 2007; 30: 596–602. Google Scholar
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006; 9: 917–24. Google Scholar
Sheridan GK, Murphy KJ. Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage. Open Biol 2013; 3: 130181. Google Scholar
O’Sullivan SA, Gasparini F, Mir AK, Dev KK. Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes. J Neuroinflamm 2016; 13: 189. Google Scholar
Llorens-Martin M, Jurado J, Hernandez F, Avila J. GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 2014; 7: 46. Google Scholar
Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, Eldar-Finkelman H. A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci Signal 2016; 9: ra110. Google Scholar
Ittner A, Chua SW, Bertz J, Volkerling A, van der Hoven J, Gladbach A, Przybyla M, Bi M, van Hummel A, Stevens CH, Ippati S, Suh LS, Macmillan A, Sutherland G, Kril JJ, Silva AP, Mackay J, Poljak A, Delerue F, Ke YD, Ittner LM. Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer’s mice. Science 2016; 354: 904–8. Google Scholar
Walter J. The Triggering receptor expressed on myeloid cells 2: a molecular link of neuroinflammation and neurodegenerative diseases. J Biol Chem 2016; 291: 4334–41. Google Scholar
Tanzi RE. TREM2 and risk of Alzheimer’s disease – friend or foe? N Engl J Med 2015; 372: 2564–5. Google Scholar
Zhong L, Chen XF, Zhang ZL, Wang Z, Shi XZ, Xu K, Zhang YW, Xu H, Bu G. DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response. J Biol Chem 2015; 290: 15866–77. Google Scholar
Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013; 155: 1451–63. Google Scholar
Rusanen M, Ngandu T, Laatikainen T, Tuomilehto J, Soininen H, Kivipelto M. Chronic obstructive pulmonary disease and asthma and the risk of mild cognitive impairment and dementia: a population based CAIDE study. Curr Alzheimer Res. 2013; 10: 549-55. Google Scholar
Chen MH, Li CT, Tsai CF, Lin WC, Chang WH, Chen TJ, Pan TL, Su TP, Bai YM. Risk of dementia among patients with asthma: a nationwide longitudinal study. J Am Med Dir Assoc 2014; 15: 763–7. Google Scholar
Wu D, Zhou J, Bi H, Li L, Gao W, Huang M, Adcock IM, Barnes PJ, Yao X. CCL11 as a potential diagnostic marker for asthma? J Asthma 2014; 51: 847–54. Google Scholar
Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park J-S, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011; 477: 90–4. Google Scholar
Lalli MA, Bettcher BM, Arcila ML, Garcia G, Guzman C, Madrigal L, Ramirez L, Acosta-Uribe J, Baena A, Wojta KJ, Coppola G, Fitch R, de Both MD, Huentelman MJ, Reiman EM, Brunkow ME, Glusman G, Roach JC, Kao AW, Lopera F, Kosik KS. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer’s disease. Mol Psychiatry 2015; 20: 1294–300. Google Scholar
Sarlus H, Hoglund CO, Karshikoff B, Wang X, Lekander M, Schultzberg M, Oprica M. Allergy influences the inflammatory status of the brain and enhances tau-phosphorylation. J Cell Mol Med 2012; 16: 2401–12. Google Scholar
Klein B, Mrowetz H, Thalhamer J, Scheiblhofer S, Weiss R, Aigner L. Allergy enhances neurogenesis and modulates microglial activation in the hippocampus. Front Cell Neurosci 2016; 10: 169. Google Scholar
About the article
Published Online: 2017-02-23
Published in Print: 2017-03-01