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Int Neurourol J > Volume 23(Suppl 2); 2019 > Article
Yang: Cellular and Molecular Mediators of Neuroinflammation in Alzheimer Disease

ABSTRACT

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the loss of neuronal cells and the progressive decline of cognitive function. The major pathological culprit of AD is aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau, eventually leading to progressive neuronal cell death and brain atrophy. However, the detailed molecular and cellular mechanisms underlying AD development as a result of neuronal cell death are little known. Although several hypotheses have been proposed regarding the development of AD, increasingly many studies suggest that the pathological progress of AD is not restricted to neuronal components such as Aβ and tau, but is also closely related to inflammatory responses in the brain. Abnormalities of Aβ and tau cause activity of pattern recognition receptors on the brain’s immune cells, including microglia and astrocytes, and trigger the innate immune system by releasing inflammatory mediators in the pathogenesis of AD. In this review, we present a basic overview of the current knowledge regarding inflammation and molecular mediators in the pathological progress of AD.

INTRODUCTION

Alzheimer disease (AD) is a neurodegenerative disease characterized by loss of neurons and synapses, leading to declines in learning and memory function in the brain [1,2]. The main hallmark of AD is the aggregation and deposition of amyloid-β (Aβ) peptides on the extracellular surface of neuronal cells, leading to the formation of Aβ oligomers and fibrils in the brain [3]. Another phenomenon observed in AD patients is hyperphosphorylation of tau protein in the brain, which accumulates in the microtubules of neurons and forms neurofibrillary tangles [4,5]. It is known that these 2 major hallmark features exert cytotoxic activities against neuronal cells, ultimately inducing the destruction of brain structure and memory decline [6,7].
Additionally, increasing evidence suggests that astrocytes and microglia are colocalized with Aβ plaques and neurofibrillary tangles in the brain of individuals with AD [8], implying that neuroinflammation may be a major component of AD pathogenesis. In epidemiological studies, AD patients who receive long-term treatment with an anti-inflammatory drug have shown diminished development of AD. Moreover, the correlation between genes regulating the immune response and AD pathogenesis has been confirmed by genome-wide association studies [9-11]. During the progression of AD, astrocytes and microglia are activated by the stimulation of Aβ plaques and neurofibrillary tangles. Activated astrocytes and microglia then migrate and surround the plaque and tangles, releasing inflammation-associated proteins such as cytokines, chemokines, and other pro-inflammatory mediators in the brain (Fig. 1) [12,13]. However, the cellular and molecular mechanisms underlying neuroinflammation in AD are not fully understood. Therefore, understanding the mechanisms that regulate neuroinflammatory processes and their impact on AD processes is important for the development of new strategies for AD treatment.

CELLULAR MEDIATORS OF NEUROINFLAMMATION IN AD

Microglia

Microglia are the resident phagocytes of the brain, where they are ubiquitously present. They contribute to protection against infection by recognizing and responding to foreign antigens, while simultaneously supporting maintenance of the brain tissue [14]. To maintain these physiological functions, including microglial homeostasis, microglia express or release various molecules during brain development and in the normal adult central nervous system (CNS). In brain development, microglia regulate apoptosis of neuronal subpopulations by CD11b, triggering receptor expressed on myeloid cells 2 (TREM2), and DAP12; release neurotrophic factors such as brain-derived neurotrophic factor; and guide sprouting vessels. Microglia also contribute to maturation of the neuronal network and the maintenance of neuronal health by releasing CX3CR1 in the adult CNS [15].
Once activated by pathological triggers such as oxidative stress or misfolded protein aggregates, microglia begin to migrate to the locus of infection and initiate the innate immune response [16,17]. The initiation of the immune response by pathological triggers is mediated by receptor binding to pattern-associated molecular patterns or danger-associated molecular patterns. It has been suggested that the initial pathological trigger of microglial activation in AD is Aβ oligomers and fibrils, which are recognized by and bind with a variety of immune receptors including CD36, CD14, and toll-like receptors (TLR2, TLR4, TLR6, and TLR9) [18-21]. This binding of Aβ with immune receptors results in microglial activation, which induces the release of several pro-inflammatory cytokines and chemokines. It has been shown that removal of the immune receptor gene CD36 results in the reduction of Aβ-induced proinflammatory cytokine production and the prevention of intracellular Aβ deposition [22,23]. Aβ oligomers and fibrils are engulfed by the phagocytosis of activated microglia, and consequently undergo endosomal/lysosomal degradation processes for the clearance of Aβ [24].
In animal models of early AD development, the immune response induces Aβ clearance through the activation of microglia, indicating that the immune response favorably regulates AD-related pathologies [25-27]. However, chronic activation of the immune response by microglia results in an aggravation of AD pathologies, such as reactive microgliosis. The continuous activation results in sustained signaling transduction by pro-inflammatory cytokines, leading to neuronal damage and resulting in the loss of phagocytosis activity by microglia and diminished breakdown of Aβ plaques [28,29].
Further compelling evidence that compromised microglial function elevates the risk of AD through mis-regulation of the inflammatory response comes from studies identifying a rare mutation in the extracellular domain of TREM2 [30-32]. TREM2 is mainly expressed by the microglia and regulates the phagocytosis of Aβ. A rare mutation in TREM2 results in substantially increased AD risk [33-35] .
In the CNS of aging animals, microglial cells show an enhanced response to inflammatory triggers, similar to that observed in microglia in individuals with an ongoing neurodegenerative disorder [36,37]. Furthermore, microglia primarily have an immunomodulatory function and express many immune response-related antigens and molecules [38]. A recent study by Zare et al. [39] studied accumulation and effects of Aβ itself, suggesting these changes may reach beyond the CNS. A transgenic mouse model showed AD mice had immunoreactivity against Alzheimer’s disease markers in the bladder. These transgenic mice not only expressed Aβ in the bladder, but also these changes were associated inducing voiding dysfunction independent of the CNS, possibly through peripheral neurogenic means. However, the detailed mechanism of microglial function within the CNS remains debatable. Given that microglial activation continuously occurs, inducing innate and adaptive immune responses in the brain, further research will be needed to define the roles of microglia during AD pathogenesis.

Astrocytes

Astrocytes are the predominant glial cells observed in the CNS and play major roles in neuroprotection, organization, and maintenance in the brain. They are involved in multiple processes in the CNS, including neurotransmitter secretion and metabolism, synaptic remodeling, modulation of stress, neural information processing, and neuronal signaling transduction [40-42]. In early AD, similar to activated microglia, activated astrocytes are located around Aβ plaques and accompany the phagocytosis and degradation of Aβ, suggesting that they play an important role in the clearance of aggregated and accumulated Aβ in brain tissue affected by AD, along with microglia [13].
In AD animal models, the early response manifests by morphological changes including the atrophy of astrocytes, which may have functional consequences for synaptic connectivity. These changes have been shown to affect astrocytes located far from senile Aβ plaques in the later phase of AD progression [43-45]. Similar to microglia, astrocytes respond to fibrillar Aβ aggregates, which are responsible for the activation of astrocytes in brain tissue affected by AD. Reactive astrocytes then release many molecular mediators such as cytokines, nitric oxide, and other potentially toxic molecules, thereby enhancing the inflammatory response in the CNS. In an animal study, direct injection of Aβ oligomers strongly induced a significant activation of astrocytes via activation of the nuclear factor-kappa B (NF-κB) transcription factor and production of inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, S100, and cyclooxygenase-2 (COX-2). By activating astrocytes, NF-κB signaling tightly regulates the production of cytokines and chemokines, leading to neurodegeneration [46].

Oligodendrocytes

Oligodendrocytes are crucial for neurotransmission and the maintenance of neuronal morphology. It also has been established that oligodendrocytes are involved in immunological reactions in other neurological diseases, particularly multiple sclerosis. However, little is known regarding the functions of oligodendrocytes in the progression of AD [47,48]. A few studies have indicated that myelin abnormalities were found in the white matter of AD patients and that focal demyelination of axons was associated with Aβ aggregation in the gray matter of AD patients, as well as in the brains of AD transgenic mice [48,49]. Another study revealed that Aβ injections induced microglial proliferation, with attenuated damage to myelin and a functional loss of oligodendrocytes [50]. In an in vitro analysis, several types of Aβ peptides, such as Aβ (25-35), Aβ (1-40), and Aβ (1-42) induced cytotoxic effects on the oligodendrocytes [48,51,52]. It was also suggested that the differentiation and function of oligodendrocytes are affected by the PS1M146V mutation and Aβ deposition [53].
Finally, oligodendrocytes express mRNA of complement components such as C1q, C1s, C2, C3, C4, C5, C6, C8, and C9, leading to a complement-associated immune response in pathologically susceptible lesions of brain tissue affected by AD [54]. Therefore, complement-activated oligodendrocytes may an important target cell type in AD patients in whom inflammatory responses have been observed.

MOLECULAR MEDIATORS OF NEUROINFLAMMATION IN AD

Complement System

The complement system is an essential mechanism of the innate and adaptive immune response against pathogens. This system consists of cell surface proteins and proteases that are cleaved and activated in a cascade [55]. The complement system is divided into 3 pathways: (1) the classical pathway induced by the binding of antibody isotypes bound to antigens, (2) the alternative pathway induced by the binding of microbial cell surfaces in the absence of antibodies, and (3) the lectin pathway induced by the binding of mannose-binding protein, which binds to surface carbohydrates on microbes. During early steps of complement activation, complement components are sequentially cleaved by C3 convertase and C5 convertase in all 3 pathways. In the late steps of activation, C5b binds to C6, C7, C8, and C9 to form the membrane attack complex (Fig. 2) [56-59].
In studies of AD, amyloid precursor protein (APP) transgenic mice in which C3 activation is inhibited have shown increased Aβ accumulation. Consistent with this finding, increased Aβ deposition was observed in the brain of C3-deficient APP transgenic mice [25,60]. Moreover, activated complement components such as C1q have been reported to recognize the aggregated forms of Aβ, but not the monomeric forms, in vitro. An Aβ aggregate bound to C1q was found to be able to activate the alternative complement pathway, leading to processing and clearance of opsonized Aβ [61,62]. It appears that the activation of complement in AD might be effective for Aβ clearance; however, it also induces the production of neurotoxic materials by concomitant undesirable inflammation. Thus, additional studies will be required to provide convincing evidence of the function of the complement system in AD development.

Cytokines

Cytokines are mainly produced by microglia and astrocytes in the CNS and play a crucial role in the development of the CNS. Cytokines are involved in numerous inflammatory responses in neurodegenerative diseases [13]. Many studies of AD patients have revealed increased levels of pro-inflammatory cytokines, including TNF and IL [63,64]. In addition, several genetic investigations in mice showed that an elevated cytokine levels are significantly correlated with microglial activation and have effects on Aβ generation, neurodegeneration, and cognition [65,66].
First, TNF-α is one of the most important pro-inflammatory cytokines in AD, having beneficial or harmful functions on different neurons. High levels of TNF-α have been reported in the brains of AD patients [67]. Aβ directly stimulates TNF-α production from microglial cells through activation of the transcription factor NF-κB [68]. TNF-α also increases the expression of β- and γ-secretase, an enzyme involved in the generation of Aβ from APP in AD development [69,70]. In addition, mice lacking TNF receptor 1 crossed with the AD transgenic model showed reduced Aβ aggregation and microglial activation, along with a recovery of cognitive function [71].
Second, IL-1 is a major pro-inflammatory cytokine that is expressed in the early stage of Aβ deposition during AD development [72]. IL-1 is produced by microglial cells surrounding Aβ plaques and promotes the synthesis of S100, an inflammatory mediator, in astrocytes [73]. Within the IL-1 family, IL-1β production is strongly observed in the brain tissue of AD patients. IL-1β regulates the synthesis of APP, the secretion of APP from glial cells, and the amyloidogenic processing of APP [70]. Additionally, elevated levels of IL-1β in AD patients promote the activation of mitogen-activated protein kinase signaling, ultimately leading to the hyperphosphorylation of tau protein [74,75].
Finally, IL-6 is important for the normal homeostasis of brain tissue. Inhibition of IL-6 signaling promotes the reduction of microglial activation, while overexpression of IL-6 leads to chronic neuroinflammation [76]. In AD mouse models (TgCRND8 and Tg2576), overexpression of IL-6 in brain tissues has been observed [26]. Similar to IL-1β, IL-6 is also produced by microglial cells and results in elevated mRNA levels of the APP gene [77]. IL-6 has also been reported to induce the hyperphosphorylation of tau protein by increasing the CDK5 activator p53, resulting in the formation of neurofibrillary tangles, which play an important role in AD pathology [78].

Chemokines

Chemokines are a family of chemoattractant small cytokines that are mainly produced by astrocytes and microglia to regulate their migration to inflamed areas, enhancing neuroinflammation in AD development [79,80]. Significant changes in chemokines and their receptors are observed in the blood plasma, cerebrospinal fluid (CSF), and brain tissue of AD patients compared with otherwise healthy individuals [81,82]. It has been reported that most chemokines and their receptors contribute to the neuroinflammation involved in AD by engaging peripheral monocytes and promoting the activation of glial cells such as microglia and astrocytes [82].
Evidence of the cooperative role of chemokines in AD has been provided by the observation of upregulation of the chemokine receptors CCR3 and CCR5 in reactive microglia surrounding senile Aβ plaques [83,84]. A recent investigation of the CSF of AD patients revealed upregulation of CCL2, which was associated with cognitive decline [85]. Moreover, in vitro analyses have shown that Aβ promoted the generation of CXCR8, CCL2, CCL3, and CCL4 in astrocytes and microglia [86]. In AD mice, the neuronal death and cognition decline induced by Aβ deposition were found to be regulated by CX3CR1 and CX3CL1 [87-89]. Therefore, it has been suggested that in AD, chemokines are able to promote central and peripheral immunity, which contributes to disease progression.

Cyclooxygenases

Given that inflammatory mediators are closely associated with the pathology of AD [72], epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), which are major inhibitors of COX, may be promising for AD drug development [90]. COX is an enzyme that is responsible for converting arachidonic acid in the process of prostaglandin synthesis. There are 2 types of COX: COX-1 and COX-2. Whereas COX-1 is expressed in many cell types and is involved in the physiological production of prostanoids, COX-2 is produced during inflammation and results in pro-inflammatory prostanoid synthesis [91,92]. COX-1 and COX2 are differently expressed in various stages of AD pathology [90]. While COX-1 is primary expressed in microglia, which are involved in Aβ aggregates in the late stage of AD, COX-2 is highly expressed in neurons and is colocalized with the expression of cell cycle proteins under conditions of low Aβ deposits and tau tangles in the early stage of AD.
In AD mice models, overexpression of COX-2 in neurons contributed to neuronal cell death by the formation of Aβ plaques and by the production of free radicals, causing aggravated cognitive deficits. Furthermore, the appearance of neuronal death in AD was inhibited by treatment with NSAIDs [91-95]. Thus, many scientists have suggested that drug development using NSAIDs to target COX-mediated neuronal cell death may be a promising potential strategy for the treatment of AD.

CONCLUSIONS

Here, we investigated neuroinflammation and consequent inflammatory mediators (cellular and molecular) in the pathological progress of AD. Inflammation is not only found in many tissues and lymphoid organs, but is also observed in neurodegenerative diseases such as AD. Many scientists have proposed that inflammation occurs in the presence of misfolded Aβ and tau proteins, resulting in initiation or acceleration of the development of the disease. However, other investigators have argued that inflammation might be a beneficial defense mechanism against neurotoxicity in brain tissue affected by AD. Whether inflammation promotes or alleviates AD, it should be acknowledged that neuroinflammation plays a major role in the development of AD. Therefore, additional studies should be conducted to define the detailed molecular mechanisms and crosstalk between neuroinflammation and AD. Therapeutic approaches targeting and regulating neuroinflammation will be a promising frontier in terms of new treatments for AD.

NOTES

Fund/Grant Support
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2015R1A6A3A04058568).
Conflict of Interest
No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Alzheimer’s Association. 2012 Alzheimer’s disease facts and figures. Alzheimers Dement 2012;8:131-68. PMID: 22404854
pmid
2. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 2007;3:186-91. PMID: 19595937
crossref pmid
3. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 2011;108:5819-24. PMID: 21421841
crossref pmid pmc
4. Schoonenboom NS, Pijnenburg YA, Mulder C, Rosso SM, Van Elk EJ, Van Kamp GJ, et al. Amyloid beta(1-42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease. Neurology 2004;62:1580-4. PMID: 15136685
crossref pmid
5. Sobow T, Flirski M, Liberski PP. Amyloid-beta and tau proteins as biochemical markers of Alzheimer’s disease. Acta Neurobiol Exp (Wars) 2004;64:53-70. PMID: 15190680
pmid
6. Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 2008;15:2321-8. PMID: 18855662
crossref pmid pmc
7. Fischer P, Zehetmayer S, Jungwirth S, Weissgram S, Krampla W, Hinterberger M, et al. Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord 2008;25:501-7. PMID: 18446027
crossref pmid
8. Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 2011;179:1373-84. PMID: 21777559
crossref pmid pmc
9. Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, et al. A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol 2015;22:1519-25. PMID: 24910016
crossref pmid
10. Budni J, Garcez ML, de Medeiros J, Cassaro E, Bellettini-Santos T, Mina F, et al. The anti-inflammatory role of minocycline in Alzheimer’s disease. Curr Alzheimer Res 2016;13:1319-29. PMID: 27539598
crossref pmid
11. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013;45:1452-8. PMID: 24162737
crossref pmid pmc pdf
12. Iversen LL, Mortishire-Smith RJ, Pollack SJ, Shearman MS. The toxicity in vitro of beta-amyloid protein. Biochem J 1995;311(Pt 1):1-16. PMID: 7575439
crossref pmid pmc pdf
13. Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V. Inflammatory process in Alzheimer’s disease. Front Integr Neurosci 2013;7:59. PMID: 23964211
pmid pmc
14. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 2011;91:461-553. crossref
15. Kierdorf K, Prinz M. Microglia in steady state. J Clin Invest 2017;127:3201-9. PMID: 28714861
crossref pmid pmc
16. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015;14:388-405. PMID: 25792098
crossref pmid pmc
17. Ji K, Akgul G, Wollmuth LP, Tsirka SE. Microglia actively regulate the number of functional synapses. PLoS One 2013;8:e56293. PMID: 23393609
crossref pmid pmc
18. Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 2003;23:2665-74. PMID: 12684452
crossref pmid pmc
19. Paresce DM, Ghosh RN, Maxfield FR. Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 1996;17:553-65. PMID: 8816718
crossref pmid
20. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155-61. PMID: 20037584
crossref pmid pdf
21. Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 2005;128(Pt 8):1778-89. PMID: 15857927
crossref pmid pdf
22. El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003;197:1657-66. PMID: 12796468
crossref pmid pmc
23. Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 2013;14:812-20. PMID: 23812099
crossref pmid pmc pdf
24. Lee CY, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna) 2010;117:949-60. PMID: 20552234
crossref pmid pmc pdf
25. Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci U S A 2002;99:10837-42. crossref
26. Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, et al. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 2010;24:548-59. PMID: 19825975
crossref pmid pmc
27. Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O’Banion MK. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 2007;117:1595-604. PMID: 17549256
crossref pmid pmc
28. Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 2008;28:8354-60. PMID: 18701698
crossref pmid pmc
29. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, et al. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995;374:647-50. PMID: 7715705
crossref pmid pdf
30. Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 2015;212:287-95. PMID: 25732305
crossref pmid pmc
31. Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 2017;12:74. PMID: 29037207
crossref pmid pmc pdf
32. Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci 2015;35:6532-43. PMID: 25904803
crossref pmid pmc
33. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013;368:117-27. PMID: 23150934
crossref pmid
34. Hickman SE, El Khoury J. TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem Pharmacol 2014;88:495-8. PMID: 24355566
crossref pmid
35. Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, et al. TREM2 is associated with increased risk for Alzheimer’s disease in African Americans. Mol Neurodegener 2015;10:19. PMID: 25886450
crossref pmid pmc
36. Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 2013;35:601-12. PMID: 23732506
crossref pmid pmc pdf
37. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 2013;39:3-18. PMID: 23252647
crossref pmid
38. Town T, Nikolic V, Tan J. The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation 2005;2:24. PMID: 16259628
crossref pmid pmc
39. Zare A. Unveiling the sensory connections between the bladder and the brain that involve the periaqueductal gray matter [dissertation]. Maastricht (Netherlands): Maastricht University; 2018. https://doi.org/10.26481/dis.20180619az.
40. Halassa MM, Haydon PG. Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 2010;72:335-55. crossref
41. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010;119:7-35. PMID: 20012068
crossref pmid pdf
42. Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature 2010;463:232-6. PMID: 20075918
crossref pmid pmc pdf
43. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 2010;58:831-8. PMID: 20140958
pmid
44. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: mechanism for deficient glutamatergic transmission? Mol Neurodegener 2011;6:55. PMID: 21801442
crossref pmid pmc
45. Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ. Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 2011;3:271-9. PMID: 22103264
pmid
46. Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM, Arevalo-Serrano J, Gonzalo-Ruiz A. Oligomers of beta-amyloid protein (Abeta1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain. Exp Neurol 2012;236:215-27. PMID: 22617488
crossref pmid
47. Kobayashi K, Hayashi M, Nakano H, Fukutani Y, Sasaki K, Shimazaki M, et al. Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer’s disease. Neuropathol Appl Neurobiol 2002;28:238-51. PMID: 12060348
crossref pmid
48. Roth AD, Ramirez G, Alarcon R, Von Bernhardi R. Oligodendrocytes damage in Alzheimer’s disease: beta amyloid toxicity and inflammation. Biol Res 2005;38:381-7. PMID: 16579521
pmid
49. Mitew S, Kirkcaldie MT, Halliday GM, Shepherd CE, Vickers JC, Dickson TC. Focal demyelination in Alzheimer’s disease and transgenic mouse models. Acta Neuropathol 2010;119:567-77. crossref pdf
50. Jantaratnotai N, Ryu JK, Kim SU, McLarnon JG. Amyloid beta peptide-induced corpus callosum damage and glial activation in vivo. Neuroreport 2003;14:1429-33. PMID: 12960758
crossref pmid
51. Xu J, Chen S, Ahmed SH, Chen H, Ku G, Goldberg MP, et al. Amyloid-beta peptides are cytotoxic to oligodendrocytes. J Neurosci 2001;21:RC118. PMID: 11150354
crossref pmid pmc
52. Lee JT, Xu J, Lee JM, Ku G, Han X, Yang DI, et al. Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol 2004;164:123-31. PMID: 14709545
crossref pmid pmc
53. Desai MK, Guercio BJ, Narrow WC, Bowers WJ. An Alzheimer’s disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction. Glia 2011;59:627-40. PMID: 21294162
crossref pmid pmc
54. Hosokawa M, Klegeris A, Maguire J, McGeer PL. Expression of complement messenger RNAs and proteins by human oligodendroglial cells. Glia 2003;42:417-23. PMID: 12730962
crossref pmid
55. Forneris F, Wu J, Gros P. The modular serine proteases of the complement cascade. Curr Opin Struct Biol 2012;22:333-41. PMID: 22560446
crossref pmid
56. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol 2013;33:479-92. PMID: 24161035
crossref pmid pmc
57. Gasque P, Singhrao SK, Neal JW, Wang P, Sayah S, Fontaine M, et al. The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis. J Immunol 1998;160:3543-54. PMID: 9531317
pmid
58. Gasque P, Ischenko A, Legoedec J, Mauger C, Schouft MT, Fontaine M. Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells. J Biol Chem 1993;268:25068-74. PMID: 8227070
crossref pmid
59. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010;11:785-97. PMID: 20720586
crossref pmid pmc pdf
60. Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 2008;28:6333-41. PMID: 18562603
crossref pmid pmc
61. Webster SD, Yang AJ, Margol L, Garzon-Rodriguez W, Glabe CG, Tenner AJ. Complement component C1q modulates the phagocytosis of Abeta by microglia. Exp Neurol 2000;161:127-38. PMID: 10683279
crossref pmid
62. Fonseca MI, Zhou J, Botto M, Tenner AJ. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci 2004;24:6457-65. PMID: 15269255
crossref pmid pmc
63. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 1995;202:17-20. PMID: 8787820
crossref pmid
64. Jiang H, Hampel H, Prvulovic D, Wallin A, Blennow K, Li R, et al. Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer’s disease. Mol Neurodegener 2011;6:69. PMID: 21978728
crossref pmid pmc
65. Meda L, Baron P, Prat E, Scarpini E, Scarlato G, Cassatella MA, et al. Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with beta-amyloid[25-35]. J Neuroimmunol 1999;93:45-52. PMID: 10378868
crossref pmid
66. Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J Neuroinflammation 2005;2:9. PMID: 15762998
crossref pmid pmc
67. Chang R, Yee KL, Sumbria RK. Tumor necrosis factor alpha Inhibition for Alzheimer’s Disease. J Cent Nerv Syst Dis 2017;9:1179573517709278. PMID: 28579870
pmid pmc
68. Combs CK, Karlo JC, Kao SC, Landreth GE. Beta-amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 2001;21:1179-88. PMID: 11160388
crossref pmid pmc
69. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B. Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol Dis 2000;7(6 Pt B):682-9. PMID: 11114266
crossref pmid
70. Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 2004;279:49523-32. PMID: 15347683
crossref pmid
71. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 2007;178:829-41. PMID: 17724122
crossref pmid pmc
72. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;21:383-421. crossref
73. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 1989;86:7611-5. PMID: 2529544
crossref pmid pmc
74. Sheng JG, Zhu SG, Jones RA, Griffin WS, Mrak RE. Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Exp Neurol 2000;163:388-91. PMID: 10833312
crossref pmid
75. Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003;23:1605-11. PMID: 12629164
crossref pmid pmc
76. Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta 2016;1863(6 Pt A):1218-27. PMID: 27016501
crossref pmid
77. Ringheim GE, Szczepanik AM, Petko W, Burgher KL, Zhu SZ, Chao CC. Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex. Brain Res Mol Brain Res 1998;55:35-44. PMID: 9645958
crossref pmid
78. Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004;295:245-57. PMID: 15051507
crossref pmid
79. Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science 1999;286:2098-102. PMID: 10617422
crossref pmid
80. Ransohoff RM. The chemokine system in neuroinflammation: an update. J Infect Dis 2002;186 Suppl 2:S152-6. PMID: 12424691
crossref pmid pdf
81. Liu C, Cui G, Zhu M, Kang X, Guo H. Neuroinflammation in Alzheimer’s disease: chemokines produced by astrocytes and chemokine receptors. Int J Clin Exp Pathol 2014;7:8342-55. PMID: 25674199
pmid pmc
82. Zuena AR, Casolini P, Lattanzi R, Maftei D. Chemokines in Alzheimer’s disease: new insights into prokineticins, chemokine-like proteins. Front Pharmacol 2019;10:622. PMID: 31231219
crossref pmid pmc
83. Ishizuka K, Kimura T, Igata-yi R, Katsuragi S, Takamatsu J, Miyakawa T. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin Neurosci 1997;51:135-8. PMID: 9225377
crossref pmid
84. Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol 1998;153:31-7. PMID: 9665462
crossref pmid pmc
85. Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O. CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS One 2012;7:e30525. PMID: 22303443
crossref pmid pmc
86. Smits HA, Rijsmus A, van Loon JH, Wat JW, Verhoef J, Boven LA, et al. Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J Neuroimmunol 2002;127:160-8. PMID: 12044988
crossref pmid
87. Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 2010;13:411-3. PMID: 20305648
crossref pmid pmc pdf
88. Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 2010;177:2549-62. PMID: 20864679
crossref pmid pmc
89. Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, et al. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem 2011;286:32713-22. PMID: 21771791
crossref pmid pmc
90. Hoozemans JJ, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P. Cyclooxygenase-1 and -2 in the different stages of Alzheimer’s disease pathology. Curr Pharm Des 2008;14:1419-27. PMID: 18537664
crossref pmid
91. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 2000;69:145-82. PMID: 10966456
crossref pmid
92. Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004;18:790-804. PMID: 15117884
crossref pmid
93. Xiang Z, Ho L, Yemul S, Zhao Z, Qing W, Pompl P, et al. Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer’s disease neuropathology. Gene Expr 2002;10:271-8. PMID: 12450219
crossref pmid
94. Xiang Z, Ho L, Valdellon J, Borchelt D, Kelley K, Spielman L, et al. Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer’s disease neuropathology. Neurobiol Aging 2002;23:327-34. PMID: 11959394
crossref pmid
95. Pasinetti GM. Cyclooxygenase and inflammation in Alzheimer’s disease: experimental approaches and clinical interventions. J Neurosci Res 1998;54:1-6. PMID: 9778144
crossref pmid

Fig. 1.
Neuroinflammation during Alzheimer disease development. In the presence of amyloid-β aggregates and neurofibrillary tangles, immune cells are activated and produce a variety of inflammatory mediators such as cytokines and chemokines.
inj-1938184-092f1.jpg
Fig. 2.
Schematic overview of the 3 complement pathways. MAC, membrane attack complex.
inj-1938184-092f2.jpg
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