[en] The triggering of innate immune mechanisms is emerging as a crucial component of major neurodegenerative diseases. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators. In this Review, we discuss how the activation of innate immune signalling pathways - in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome - by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders. During chronic activation of microglia, the sustained exposure of neurons to pro-inflammatory mediators can cause neuronal dysfunction and contribute to cell death. As chronic neuroinflammation is observed at relatively early stages of neurodegenerative disease, targeting the mechanisms that drive this process may be useful for diagnostic and therapeutic purposes.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; 1] Clinical Neuroscience, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. [2] Department of Internal Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA. [3] German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany
Kummer, Markus P; Clinical Neuroscience, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Latz, Eicke; 1] Department of Internal Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA. [2] German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. [3] Institute of Innate Immunity, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Innate immune activation in neurodegenerative disease.
Publication date :
July 2014
Journal title :
Nature Reviews. Immunology
ISSN :
1474-1733
eISSN :
1474-1741
Publisher :
Nature Publishing Group, Basingstoke, Hampshire, England
The authors’ work was supported by grants to M.T.H. and E.L. from the German Research Council (Deutsche Forschungsgemeinschaft, KFO177 and Cluster of Excellence “Immunosensation”).
Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nature Neurosci. 16, 273-280 (2013).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841-845 (2010).
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. 117, 145-152 (1999).
Lawson, L. J., Perry, V. H., Dri, P. & Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151-170 (1990).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596-1609 (2013).
Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974-3980 (2009).
Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456-1458 (2011).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691-705 (2012).
Rigato, C., Buckinx, R., Le-Corronc, H., Rigo, J. M. & Legendre, P. Pattern of invasion of the embryonic mouse spinal cord by microglial cells at the time of the onset of functional neuronal networks. Glia 59, 675-695 (2011).
Tremblay, M.-E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
Vukovic, J., Colditz, M. J., Blackmore, D. G., Ruitenberg, M. J. & Bartlett, P. F. Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J. Neurosci. 32, 6435-6443 (2012).
Fellner, L. et al. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61, 349-360 (2013).
Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunol. 11, 155-161 (2010).
Udan, M. L. D., Ajit, D., Crouse, N. R. & Nichols, M. R. Toll-like receptors 2 and 4 mediate Aβ(1-42) activation of the innate immune response in a human monocytic cell line. J. Neurochem. 104, 524-533 (2008).
Jin, J.-J., Kim, H.-D., Maxwell, J. A., Li, L. & Fukuchi, K.-I. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J. Neuroinflamm. 5, 23 (2008).
Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nature Rev. Immunol. 13, 397-411 (2013).
Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278-286 (2012).
De Rivero Vaccari, J. P. et al. Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J. Cereb. Blood Flow Metab. 29, 1251-1261 (2009).
Adamczak, S. E. et al. Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J. Cereb. Blood Flow Metab. 34, 621-629 (2014).
Minkiewicz, J., de Rivero Vaccari, J. P. & Keane, R. W. Human astrocytes express a novel NLRP2 inflammasome. Glia 61, 1113-1121 (2013).
Shimohama, S. et al. Activation of NADPH oxidase in Alzheimer's disease brains. Biochem. Biophys. Res. Commun. 273, 5-9 (2000).
Reynolds, W. F. et al. Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease. Exp. Neurol. 155, 31-41 (1999).
Heneka, M. T. et al. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 906-916 (2001).
Vodovotz, Y. et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease. J. Exp. Med. 184, 1425-1433 (1996).
Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760-1765 (2003).
Nagatsu, T. & Sawada, M. Inflammatory process in Parkinson's disease: role for cytokines. Curr. Pharm. Des. 11, 999-1016 (2005).
Alirezaei, M., Kiosses, W. B., Flynn, C. T., Brady, N. R. & Fox, H. S. Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS ONE 3, e2906 (2008).
Koenigsknecht-Talboo, J. & Landreth, G. E. Microglial phagocytosis induced by fibrillar β-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 25, 8240-8249 (2005).
Sheng, J. G. et al. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid-β peptide in APPswe transgenic mice. Neurobiol. Dis. 14, 133-145 (2003).
Qiao, X., Cummins, D. J. & Paul, S. M. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur. J. Neurosci. 14, 474-482 (2001).
Jack, C. R. Jr et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207-216 (2013).
Querfurth, H. W. & LaFerla, F. M. Alzheimer's disease. N. Engl. J. Med. 362, 329-344 (2010).
Bertram, L., Lill, C. M. & Tanzi, R. E. The genetics of Alzheimer disease: back to the future. Neuron 68, 270-281 (2010).
Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774-1774 (2010).
Breitner, J. C. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer's disease. Annu. Rev. Med. 47, 401-411 (1996).
Sastre, M. et al. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretase. J. Neurosci. 23, 9796-9804 (2003).
Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212-216 (2001).
in t' Veld, B. A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345, 1515-1521 (2001).
Iwashyna, T. J., Ely, E. W., Smith, D. M. & Langa, K. M. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304, 1787-1794 (2010).
Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768-774 (2009).
Semmler, A. et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J. Neurol. Neurosurg. Psychiatr. 84, 62-69 (2012).
Whitmer, R. A., Gunderson, E. P., Quesenberry, C. P. Jr, Zhou, J. & Yaffe, K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr. Alzheimer Res. 4, 103-109 (2007).
Larson, E. B. et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann. Intern. Med. 144, 73-81 (2006).
Scarmeas, N. et al. Physical activity, diet, and risk of Alzheimer disease. JAMA 302, 627-637 (2009).
Kamer, A. R. et al. TNF-á and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects. J. Neuroimmunol. 216, 92-97 (2009).
Kamer, A. R. et al. Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement. 4, 242-250 (2008).
Sparks Stein, P. et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease. Alzheimers Dement. 8, 196-203 (2012).
Cagnin, A. et al. In-vivo measurement of activated microglia in dementia. Lancet 358, 461-467 (2001).
Yasuno, F. et al. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [11C]DAA1106. Psychiatry Res. 203, 67-74 (2012).
Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707-720 (2013).
Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094-1099 (2009).
Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet. 43, 429-435 (2011).
Liang, Y. & Tedder, T. F. Identification of a CD20-, FcεRIβ-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse. Genomics 72, 119-127 (2001).
Lajaunias, F., Dayer, J.-M. & Chizzolini, C. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur. J. Immunol. 35, 243-251 (2005).
Bradshaw, E. M. et al. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nature Neurosci. 16, 848-850 (2013).
Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631-643 (2013).
Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117-127 (2013).
Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107-116 (2013).
Frank, S. et al. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56, 1438-1447 (2008).
Melchior, B. et al. Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease. ASN Neuro. 2, e00037 (2010).
Bouchon, A., Hernndez-Munain, C., Cella, M. & Colonna, M. A. DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194, 1111-1122 (2001).
Hamerman, J. A. et al. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J. Immunol. 177, 2051-2055 (2006).
Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation. Nature Immunol. 14, 812-820 (2013).
Chapman, M. R. et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295, 851-855 (2002).
Epstein, E. A. & Chapman, M. R. Polymerizing the fibre between bacteria and host cells: the biogenesis of functional amyloid fibres. Cell. Microbiol. 10, 1413-1420 (2008).
Hammer, N. D. et al. The C-terminal repeating units of CsgB direct bacterial functional amyloid nucleation. J. Mol. Biol. 422, 376-389 (2012).
Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857-865 (2008).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674-678 (2013).
Tong, L. et al. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase. J. Neurosci. 32, 17714-17724 (2012).
Cameron, B. 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. 32, 15112-15123 (2012).
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neurosci. 8, 752-758 (2005).
Wu, Z. et al. Differential pathways for interleukin-1β production activated by chromogranin A and amyloid-β in microglia. Neurobiol. Aging 34, 2715-2725 (2013).
Shepherd, C. E. et al. Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease. Neurobiol. Aging 27, 1554-1563 (2006).
Kummer, M. P. et al. Mrp14 deficiency ameliorates amyloid-β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing. J. Neurosci. 32, 17824-17829 (2012).
Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nature Med. 18, 1812-1819 (2012).
Terwel, D. et al. Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis. J. Neurosci. 31, 7049-7059 (2011).
Kummer, M. P. et al. Nitration of tyrosine 10 critically enhances amyloid-β aggregation and plaque formation. Neuron 71, 833-844 (2011).
Serrano-Pozo, A., G ñmez-Isla, T., Growdon, J. H., Frosch, M. P. & Hyman, B. T. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am. J. Pathol. 182, 2332-2344 (2013).
El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Med. 13, 432-438 (2007).
Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159-11171 (2011).
Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N. & LaFerla, F. M. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J. Neurosci. 25, 8843-8853 (2005).
Lee, C. Y. D. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949-960 (2010).
Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-351 (2007).
Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19-31 (2010).
Van Langenhove, T., van der Zee, J. & Van Broeckhoven, C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann. Med. 44, 817-828 (2012).
Mackenzie, I. R. A. et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 119, 1-4 (2010).
Sjögren, M., Folkesson, S., Blennow, K. & Tarkowski, E. Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications. J. Neurol. Neurosurg. Psychiatr. 75, 1107-1111 (2004).
Cagnin, A., Rossor, M., Sampson, E. L., Mackinnon, T. & Banati, R. B. In vivo detection of microglial activation in frontotemporal dementia. Ann. Neurol. 56, 894-897 (2004).
Rayaprolu, S. et al. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol. Neurodegener. 8, 19 (2013).
Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916-919 (2006).
Petkau, T. L. et al. Progranulin expression in the developing and adult murine brain. J. Comp. Neurol. 518, 3931-3947 (2010).
Chen-Plotkin, A. S. et al. Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta Neuropathol. 119, 111-122 (2010).
Kleinberger, G., Capell, A., Haass, C. & Van Broeckhoven, C. Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol. Neurobiol. 47, 337-360 (2013).
Pickford, F. et al. Progranulin is a chemoattractant for microglia and stimulates their endocytic activity. Am. J. Pathol. 178, 284-295 (2011).
Martens, L. H. et al. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J. Clin. Invest. 122, 3955-3959 (2012).
Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J. Exp. Med. 207, 117-128 (2010).
Hosler, B. A. et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284, 1664-1669 (2000).
Petkau, T. L. et al. Synaptic dysfunction in progranulin-deficient mice. Neurobiol. Dis. 45, 711-722 (2012).
Gerhard, A. et al. [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 61, 686-689 (2003).
Mogi, M. et al. Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients. Neurosci. Lett. 180, 147-150 (1994).
Damier, P., Hirsch, E. C., Zhang, P., Agid, Y. & Javoy-Agid, F. Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 52, 1-6 (1993).
Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol. 8, 382-397 (2009).
Hamza, T. H. et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nature Genet. 42, 781-785 (2010).
International Parkinson Disease Genomics Consortium. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377, 641-649 (2011).
Noelker, C. et al. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci. Rep. 3, 1393 (2013).
McCoy, M. K. et al. Intranigral lentiviral delivery of dominant negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol. Ther. 16, 1572-1579 (2008).
Zhang, W. et al. Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 19, 533-542 (2005).
Wu, D.-C. 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. USA 100, 6145-6150 (2003).
Hunot, S. et al. Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72, 355-363 (1996).
Giasson, B. I. et al. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science 290, 985-989 (2000).
Shavali, S., Combs, C. K. & Ebadi, M. Reactive macrophages increase oxidative stress and alpha-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson's disease. Neurochem. Res. 31, 85-94 (2006).
Chung, C. Y. et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983-987 (2013).
Theodore, S., Cao, S., McLean, P. J. & Standaert, D. G. 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. 67, 1149-1158 (2008).
Harms, A. S. et al. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592-9600 (2013).
Codolo, G. et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8, e55375 (2013).
B?raud, D. et al. α-synuclein alters Toll-like receptor expression. Front. Neurosci. 5, 80 (2011).
Talbot, K. Motor neurone disease. Postgrad. Med. J. 78, 513-519 (2002).
Kawamata, T., Akiyama, H., Yamada, T. & McGeer, P. L. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 140, 691-707 (1992).
Frakes, A. E. et al. Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron 81, 1009-1023 (2014).
Brettschneider, J. et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7, e39216 (2012).
Zhao, W. et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 58, 231-243 (2010).
Boill?e, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392 (2006).
Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113-117 (2003).
Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neurosci. 11, 251-253 (2008).
Meissner, F., Molawi, K. & Zychlinsky, A. Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis. Proc. Natl Acad. Sci. USA 107, 13046-13050 (2010).
Izecka, J., Stelmasiak, Z. & Dobosz, B. Interleukin-1β converting enzyme/Caspase-1 (ICE/Caspase-1) and soluble APO-1/Fas/CD 95 receptor in amyotrophic lateral sclerosis patients. Acta Neurol. Scand. 103, 255-258 (2001).
Pasinelli, P., Borchelt, D. R., Houseweart, M. K., Cleveland, D. W. & Brown, R. H. Jr. Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc. Natl Acad. Sci. USA 95, 15763-15768 (1998).
Han, P. & Whelan, P. J. Tumor necrosis factor alpha enhances glutamatergic transmission onto spinal motoneurons. J. Neurotrauma 27, 287-292 (2010).
Sargsyan, S. A. et al. A comparison of in vitro properties of resting SOD1 transgenic microglia reveals evidence of reduced neuroprotective function. BMC Neurosci. 12, 91 (2011).
Nguyen, M. D., D'Aigle, T., Gowing, G., Julien, J.-P. & Rivest, S. Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 24, 1340-1349 (2004).
Kiaei, M., Kipiani, K., Chen, J., Calingasan, N. Y. & Beal, M. F. Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp. Neurol. 191, 331-336 (2005).
Schátz, B. et al. The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J. Neurosci. 25, 7805-7812 (2005).
Dupuis, L. et al. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS ONE 7, e37885 (2012).
Wilcock, G. K. et al. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol. 7, 483-493 (2008).
Levine, T. D. et al. A pilot trial of pioglitazone HCl and tretinoin in ALS: cerebrospinal fluid biomarkers to monitor drug efficacy and predict rate of disease progression. Neurol. Res. Int. 2012, 1-6 (2012).
Singhrao, S. K., Neal, J. W., Morgan, B. P. & Gasque, P. Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease. Exp. Neurol. 159, 362-376 (1999).
Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263-267 (1999).
Dalrymple, A. et al. Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and biomarker candidates. J. Proteome Res. 6, 2833-2840 (2007).
Björkqvist, M. et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J. Exp. Med. 205, 1869-1877 (2008).
Silvestroni, A., Faull, R. L. M., Strand, A. D. & Möller, T. Distinct neuroinflammatory profile in post-mortem human Huntington's disease. Neuroreport 20, 1098-1103 (2009).
Tai, Y. F. et al. Microglial activation in presymptomatic Huntington's disease gene carriers. Brain 130, 1759-1766 (2007).
Simmons, D. A. et al. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease. Glia 55, 1074-1084 (2007).
Crotti, A. et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nature Neurosci. 17, 513-521 (2014).
Wild, E. et al. Abnormal peripheral chemokine profile in Huntington's disease. PLoS Curr. 3, RRN1231 (2011).
Crocker, S. F., Costain, W. J. & Robertson, H. A. DNA microarray analysis of striatal gene expression in symptomatic transgenic Huntington's mice (R6/2) reveals neuroinflammation and insulin associations. Brain Res. 1088, 176-186 (2006).
Kraft, A. D., Kaltenbach, L. S., Lo, D. C. & Harry, G. J. Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons. Neurobiol. Aging 33, 621.e17-621.e33 (2012).
Kwan, W. et al. Mutant huntingtin impairs immune cell migration in Huntington disease. J. Clin. Invest. 122, 4737-4747 (2012).
Khoshnan, A. et al. Activation of the IκB kinase complex and nuclear factor-κB contributes to mutant huntingtin neurotoxicity. J. Neurosci. 24, 7999-8008 (2004).
Palazuelos, J. et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity. Brain 132, 3152-3164 (2009).
Bradford, J. et al. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. PNAS 106, 22480-22485 (2009).
Shin, J.-Y. et al. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001-1012 (2005).
Richards, R. I., Samaraweera, S. E., van Eyk, C. L., O'Keefe, L. V. & Suter, C. M. RNA pathogenesis via Toll-like receptor-activated inflammation in expanded repeat neurodegenerative diseases. Front. Mol. Neurosci. 6, 25 (2013).
Samaraweera, S. E., O'Keefe, L. V., Price, G. R., Venter, D. J. & Richards, R. I. Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases. Hum. Mol. Genet. 22, 2811-2819 (2013).
Shepherd, C. E., Thiel, E., McCann, H., Harding, A. J. & Halliday, G. M. Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies. Arch. Neurol. 57, 817-822 (2000).
Mackenzie, I. R. Activated microglia in dementia with Lewy bodies. Neurology 55, 132-134 (2000).
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 23, 9-15 (2003).
Rozemuller, A. J., Eikelenboom, P., Theeuwes, J. W., Jansen Steur, E. N. & de Vos, R. A. Activated microglial cells and complement factors are unrelated to cortical Lewy bodies. Acta Neuropathol. 100, 701-708 (2000).
Rüb, U. et al. The nucleus raphe interpositus in spinocerebellar ataxia type 3 (Machado-Joseph disease). J. Chem. Neuroanat. 25, 115-127 (2003).
Petersen, A. J., Rimkus, S. A. & Wassarman, D. A. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila. Proc. Natl Acad. Sci. USA 109, E656-E664 (2012).
Petersen, A. J., Katzenberger, R. J. & Wassarman, D. A. The innate immune response transcription factor relish is necessary for neurodegeneration in a Drosophila model of ataxia-telangiectasia. Genetics 194, 133-142 (2013).
Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).
Jankowsky, J. L. et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17, 157-165 (2001).
Jackson-Lewis, V. & Przedborski, S. Protocol for the MPTP mouse model of Parkinson's disease. Nature Protocols 2, 141-151 (2007).
Ungerstedt, U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur. J. Pharmacol. 5, 107-110 (1968).
St Martin, J. L. et al. Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. J. Neurochem. 100, 1449-1457 (2007).
Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264, 1772-1775 (1994).
Wong, P. C. et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105-1116 (1995).
Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493-506 (1996).
