Neuroinflammation bei neurodegenerativen Erkrankungen

A. Traschütz; M. T. Heneka

doi:10.1055/s-0035-1552714

Aktuelle Neurologie, Inhaltsverzeichnis

Aktuelle Neurologie 2015; 42(07): 402-410
DOI: 10.1055/s-0035-1552714

Übersicht

Neuroinflammation bei neurodegenerativen Erkrankungen

Neuroinflammation in Neurodegenerative Disease

A. Traschütz

¹Universitätsklinikum Bonn, Klinik und Poliklinik für Neurologie, AG Klinische Neurowissenschaften, Bonn

,

M. T. Heneka

¹Universitätsklinikum Bonn, Klinik und Poliklinik für Neurologie, AG Klinische Neurowissenschaften, Bonn

²Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn

› Institutsangaben

Abstract

Zusammenfassung

Bei einigen neurodegenerativen Erkrankungen kristallisieent sich inflammatorischer Mechanismen zunehmend als wesentliche Komponente der Krankheitsentstehung und -entwicklung heraus. Mikrogliazellen als Repräsentanten des angeborenen Immunsystems im ZNS werden dabei durch Aggregate aus fehlgefalteten Proteinen oder Nukleinsäuren stimuliert. Aus deren neuroprotektiver und homöostatischer Wirkung unter physiologischen Bedingungen entsteht ein chronischer Entzündungsprozess, der über proinflammatorische Zytokine zum neuronalen Zelluntergang beiträgt. In diesem Artikel geben wir eine Übersicht über den gegenwärtigen Kenntnisstand neuroinflammatorischer Mechanismen bei zentralen neurodegenerativen Krankheiten. Da Neuroinflammation schon früh und zum Teil vor dem Eintreten der manifesten Erkrankung einsetzt, sind die beteiligten Mechanismen attraktive Angriffspunkte für zukünftige Behandlungsansätze. Einige davon werden am Ende des Artikels kurz vorgestellt.

Abstract

Increasing evidence indicates that inflammatory mechanisms play a major role in the development and progression of neurodegenerative diseases. Aggregates of misfolded proteins or nucleic acids stimulate microglial cells as representatives of the innate immune system in the central nervous system. This activation diverts microglia from their neuroprotective and homeostatic functions under physiological conditions to a chronic inflammatory state in which pro-inflammatory cytokines contribute to neuronal cell death. In the present article, we provide an overview of the current knowledge of neuroinflammatory mechanisms in major neurodegenerative diseases. As signs of neuroinflammation can be found before the onset of symptoms in many disorders, the underlying mechanisms offer promising targets for future therapeutic approaches. Some of them are briefly discussed at the end of the article.

Schlüsselwörter

Neuroinflammation - Neurodegeneration - Demenz - Alzheimer-Krankheit - Parkinson-Krankheit - amyotrophe Lateralsklerose - Chorea Huntington

Keywords

neuroinflammation - neurodegeneration - dementia - Alzheimer’s disease - Parkinson’s disease - amyotrophic lateral sclerosis - Huntington’s disease

Volltext

Referenzen

Literatur
1 Ransohoff RM, Cardona AE. The myeloid cells of the central nervous system parenchyma. Nature 2010; 468: 253-262
2 Hammett ST, Thompson PG, Bedingham S. The dynamics of velocity adaptation in human vision. Curr Biol 2000; 10: 1123-1126
3 Ginhoux F, Greter M, Leboeuf M et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330: 841-845
4 Alliot F, Godin I, Pessac B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 1999; 117: 145-152
5 Lawson LJ, Perry VH, Dri P et al. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 1990; 39: 151-170
6 Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314-1318
7 Rigato C, Buckinx R, Le-Corronc H et al. Pattern of invasion of the embryonic mouse spinal cord by microglial cells at the time of the onset of functional neuronal networks. Glia 2011; 59: 675-695
8 Wake H, Moorhouse AJ, Jinno S et al. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 2009; 29: 3974-3980
9 Tremblay ME, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol 2010; 8: e1000527
10 Parkhurst CN, Yang G, Ninan I et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013; 155: 1596-1609
11 Vukovic J, Colditz MJ, Blackmore DG et al. Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J Neurosci 2012; 32: 6435-6443
12 Fellner L, Irschick R, Schanda K et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 2013; 61: 349-360
13 Stewart CR, Stuart LM, Wilkinson K et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11: 155-161
14 Udan ML, Ajit D, Crouse NR et al. Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. J Neurochem 2008; 104: 524-533
15 Jin JJ, Kim HD, Maxwell JA et al. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 2008; 5: 23
16 Chapman MR, Robinson LS, Pinkner JS et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 2002; 295: 851-855
17 Streit WJ, Sammons NW, Kuhns AJ et al. Dystrophic microglia in the aging human brain. Glia 2004; 45: 208-212
18 Letiembre M, Hao W, Liu Y et al. Innate immune receptor expression in normal brain aging. Neuroscience 2007; 146: 248-254
19 Frank MG, Barrientos RM, Biedenkapp JC et al. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging 2006; 27: 717-722
20 Sheng JG, Mrak RE, Griffin WS. Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta neuropathol 1998; 95: 229-234
21 Shimohama S, Tanino H, Kawakami N et al. Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 2000; 273: 5-9
22 Heneka MT, Wiesinger H, Dumitrescu-Ozimek L et al. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60: 906-916
23 Vodovotz Y, Lucia MS, Flanders KC et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med 1996; 184: 1425-1433
24 Latz E. The inflammasomes: mechanisms of activation and function. Curr Opin Immunol 2010; 22: 28-33
25 Strowig T, Henao-Mejia J, Elinav E et al. Inflammasomes in health and disease. Nature 2012; 481: 278-286
26 Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 1760-1765
27 Alirezaei M, Kiosses WB, Flynn CT et al. Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS One 2008; 3: e2906
28 Nagatsu T, Sawada M. Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 2005; 11: 999-1016
29 Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 2005; 25: 8240-8249
30 Qiao X, Cummins DJ, Paul SM. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci 2001; 14: 474-482
31 Haga S, Akai K, Ishii T. Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody. Acta Neuropathol 1989; 77: 569-575
32 Querfurth HW, LaFerla FM. Alzheimer’s disease. New Engl J Med 2010; 362: 329-344
33 Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 2010; 68: 270-281
34 Mawuenyega KG, Sigurdson W, Ovod V et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 2010; 330: 1774
35 El Khoury JB, Moore KJ, Means TK et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003; 197: 1657-1666
36 Halle A, Hornung V, Petzold GC et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 2008; 9: 857-865
37 Sheedy FJ, Grebe A, Rayner KJ et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 2013; 14: 812-820
38 Griffin WS, Stanley LC, Ling C 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: 7611-7615
39 Blum-Degen D, Muller T, Kuhn W et al. 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
40 Tong L, Prieto GA, Kramar EA et al. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1beta via p38 mitogen-activated protein kinase. J Neurosci 2012; 32: 17714-17724
41 Cameron B, Tse W, Lamb R et al. Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer’s disease. J Neurosci 2012; 32: 15112-15123
42 Heneka MT, Kummer MP, Stutz A et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493: 674-678
43 Pautz A, Art J, Hahn S et al. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 2010; 23: 75-93
44 Kummer MP, Hermes M, Delekarte A et al. Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron 2011; 71: 833-844
45 Kitazawa M, Oddo S, Yamasaki TR et al. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci 2005; 25: 8843-8853
46 Yoshiyama Y, Higuchi M, Zhang B et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007; 53: 337-351
47 Bhaskar K, Konerth M, Kokiko-Cochran ON et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010; 68: 19-31
48 Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Z für gesamte Neurol Psychiatr 2011; 4: 356-385
49 Cagnin A, Brooks DJ, Kennedy AM et al. In-vivo measurement of activated microglia in dementia. Lancet 2001; 358: 461-467
50 Yasuno F, Kosaka J, Ota M et al. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [¹¹C]DAA1106. Psychiatry Res 2012; 203: 67-74
51 Breitner JC. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med 1996; 47: 401-411
52 in t’ Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. New Engl J Med 2001; 345: 1515-1521
53 Iwashyna TJ, Ely EW, Smith DM et al. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304: 1787-1794
54 Holmes C, Cunningham C, Zotova E et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009; 73: 768-774
55 Whitmer RA, Gunderson EP, Quesenberry Jr CP et al. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 2007; 4: 103-109
56 Larson EB, Wang L, Bowen JD et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 2006; 144: 73-81
57 Scarmeas N, Luchsinger JA, Schupf N et al. Physical activity, diet, and risk of Alzheimer disease. JAMA 2009; 302: 627-637
58 Kamer AR, Craig RG, Dasanayake AP et al. Inflammation and Alzheimer’s disease: possible role of periodontal diseases. Alzheimers Dement 2008; 4: 242-250
59 Semmler A, Widmann CN, Okulla T et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013; 84: 62-69
60 Sivanandam TM, Thakur MK. Traumatic brain injury: a risk factor for Alzheimer’s disease. Neurosci Biobehav Rev 2012; 36: 1376-1381
61 Zhang B, Gaiteri C, Bodea L-G et al. Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease. Cell 2013; 153: 707-720
62 Lambert JC, Heath S, Even G et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Gen 2009; 41: 1094-1099
63 Hollingworth P, Harold D, Sims R et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Gen 2011; 43: 429-435
64 Bradshaw EM, Chibnik LB, Keenan BT et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 2013; 16: 848-850
65 Griciuc A, Serrano-Pozo A, Parrado A et al. Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta. Neuron 2013; 78: 631-643
66 Guerreiro R, Wojtas A, Bras J et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013; 368: 117-127
67 Jonsson T, Stefansson H, Steinberg S et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013; 368: 107-116
68 McGeer PL, Itagaki S, Boyes BE et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988; 38: 1285-1291
69 Hunot S, Dugas N, Faucheux B et al. FcepsilonRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J Neurosci 1999; 19: 3440-3447
70 Gerhard A, Pavese N, Hotton G et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 2006; 21: 404-412
71 Mogi M, Harada M, Riederer P et al. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 1994; 165: 208-210
72 Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection?. Lancet Neurol 2009; 8: 382-397
73 Hamza TH, Zabetian CP, Tenesa A et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Gen 2010; 42: 781-785
74 Rayaprolu S, Mullen B, Baker M et al. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease. Mol Neurodegener 2013; 8: 19
75 Zhang W, Wang T, Pei Z et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 2005; 19: 533-542
76 Codolo G, Plotegher N, Pozzobon T et al. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS One 2013; 8: e55375
77 Theodore S, Cao S, McLean PJ et al. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 2008; 67: 1149-1158
78 Harms AS, Cao S, Rowse AL et al. MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci 2013; 33: 9592-9600
79 Noelker C, Morel L, Lescot T et al. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci Rep 2013; 3: 1393
80 McCoy MK, Ruhn KA, Martinez TN et al. Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol Ther 2008; 16: 1572-1579
81 Hunot S, Boissiere F, Faucheux B et al. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 1996; 72: 355-363
82 Wu DC, Teismann P, Tieu K et al. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci U S A 2003; 100: 6145-6150
83 Giasson BI, Duda JE, Murray IV et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290: 985-989
84 Damier P, Hirsch EC, Zhang P et al. Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 1993; 52: 1-6
85 Gao HM, Zhang F, Zhou H et al. Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. Environ Health Perspect 2011; 119: 807-814
86 Talbot K. Motor neurone disease. Postgrad Med J 2002; 78: 513-519
87 Kawamata T, Akiyama H, Yamada T et al. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 1992; 140: 691-707
88 Brettschneider J, Toledo JB, Van Deerlin VM et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One 2012; 7: e39216
89 Turner MR, Cagnin A, Turkheimer FE et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 2004; 15: 601-609
90 Frakes AE, Ferraiuolo L, Haidet-Phillips AM et al. Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 2014; 81: 1009-1023
91 Zhao W, Beers DR, Henkel JS et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 2010; 58: 231-243
92 Meissner F, Molawi K, Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A 2010; 107: 13046-13050
93 Ilzecka J, Stelmasiak Z, Dobosz B. Interleukin-1beta converting enzyme/Caspase-1 (ICE/Caspase-1) and soluble APO-1/Fas/CD 95 receptor in amyotrophic lateral sclerosis patients. Acta Neurol Scand 2001; 103: 255-258
94 Pasinelli P, Borchelt DR, Houseweart MK et al. Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A 1998; 95: 15763-15768
95 Boillee S, Yamanaka K, Lobsiger CS et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006; 312: 1389-1392
96 Clement AM, Nguyen MD, Roberts EA et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003; 302: 113-117
97 Yamanaka K, Chun SJ, Boillee S et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 2008; 11: 251-253
98 Nguyen MD, D’Aigle T, Gowing G et al. Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J Neurosci 2004; 24: 1340-1349
99 Kiaei M, Kipiani K, Chen J et al. Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 2005; 191: 331-336
100 Schutz B, Reimann J, Dumitrescu-Ozimek L et al. The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci 2005; 25: 7805-7812
101 Dupuis L, Dengler R, Heneka MT et al. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS One 2012; 7: e37885
102 Singhrao SK, Neal JW, Morgan BP et al. Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp Neurol 1999; 159: 362-376
103 Ona VO, Li M, Vonsattel JP et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999; 399: 263-267
104 Bjorkqvist M, Wild EJ, Thiele J et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 2008; 205: 1869-1877
105 Silvestroni A, Faull RL, Strand AD et al. Distinct neuroinflammatory profile in post-mortem human Huntington’s disease. Neuroreport 2009; 20: 1098-1103
106 Dalrymple A, Wild EJ, Joubert R et al. Proteomic profiling of plasma in Huntington’s disease reveals neuroinflammatory activation and biomarker candidates. J Proteome Res 2007; 6: 2833-2840
107 Wild E, Magnusson A, Lahiri N et al. Abnormal peripheral chemokine profile in Huntington’s disease. PLoS Curr 2011; 3: RRN1231
108 Tai YF, Pavese N, Gerhard A et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 2007; 130: 1759-1766
109 Crocker SF, Costain WJ, Robertson HA. DNA microarray analysis of striatal gene expression in symptomatic transgenic Huntington’s mice (R6/2) reveals neuroinflammation and insulin associations. Brain Res 2006; 1088: 176-186
110 Kraft AD, Kaltenbach LS, Lo DC et al. Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons. Neurobiol Aging 2012; 33: 621 e617-633
111 Khoshnan A, Ko J, Watkin EE et al. Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J Neurosci 2004; 24: 7999-8008
112 Richards RI, Samaraweera SE, van Eyk CL et al. RNA pathogenesis via Toll-like receptor-activated inflammation in expanded repeat neurodegenerative diseases. Front Mol Neurosci 2013; 6: 25
113 Samaraweera SE, O’Keefe LV, Price GR et al. Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases. Hum Mol Genet 2013; 22: 2811-2819
114 Simmons DA, Casale M, Alcon B et al. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia 2007; 55: 1074-1084
115 Bradford J, Shin JY, Roberts M et al. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A 2009; 106: 22480-22485
116 Shin JY, Fang ZH, Yu ZX et al. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 2005; 171: 1001-1012
117 Mackenzie IR. Activated microglia in dementia with Lewy bodies. Neurology 2000; 55: 132-134
118 Katsuse O, Iseki E, Kosaka K. Immunohistochemical study of the expression of cytokines and nitric oxide synthases in brains of patients with dementia with Lewy bodies. Neuropathology 2003; 23: 9-15
119 Cuyvers E, Bettens K, Philtjens S et al. Investigating the role of rare heterozygous TREM2 variants in Alzheimer’s disease and frontotemporal dementia. Neurobiol Aging 2014; 35: 726 e711-729
120 Cagnin A, Rossor M, Sampson EL et al. In vivo detection of microglial activation in frontotemporal dementia. Ann Neurol 2004; 56: 894-897
121 Gerhard A, Banati RB, Goerres GB et al. [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 2003; 61: 686-689
122 Rub U, Brunt ER, Gierga K et al. The nucleus raphe interpositus in spinocerebellar ataxia type 3 (Machado-Joseph disease). J Chem Neuroanat 2003; 25: 115-127
123 Gilman S, Koller M, Black RS et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64: 1553-1562
124 Doody RS, Thomas RG, Farlow M et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 311-321
125 Salloway S, Sperling R, Fox NC et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322-333
126 Adolfsson O, Pihlgren M, Toni N et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 2012; 32: 9677-9689
127 Takata K, Kitamura Y, Saeki M et al. Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem 2010; 285: 40180-40191
128 Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci 2012; 32: 10117-10128
129 Heneka MT, Fink A, Doblhammer G. Effect of pioglitazone medication on the incidence of dementia. Ann Neurol 2015;
130 Vom Berg J, Prokop S, Miller KR et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 2012; 18: 1812-1819