Review: Astrocytes in Alzheimer's disease and other age-associated dementias: a supporting player with a central role

Neuropathology and Applied Neurobiology

Volumn 43, Issue 4, 2017, Pages 281-298

  Garwood, C J ^a   Ratcliffe, L E ^a   Simpson, J E ^a   Heath, P R ^a   Ince, P G ^a   Wharton, S B ^a  

^a UNIVERSITY OF SHEFFIELD   (United Kingdom)

Author keywords

Alzheimer's disease; astrocytes; dementia; neurodegeneration; neurovascular unit

Indexed keywords

ALDH1L1 PROTEIN; AMINO ACID TRANSPORTER; AMYLOID BETA PROTEIN; APOLIPOPROTEIN E; ENDOTHELIN 1; EXCITATORY AMINO ACID TRANSPORTER 1; EXCITATORY AMINO ACID TRANSPORTER 2; GLIAL FIBRILLARY ACIDIC PROTEIN; GLUTAMATE AMMONIA LIGASE; HERMES ANTIGEN; N MYC DOWN REGULATED GENE 2; NDRG2 PROTEIN; NEUROTRANSMITTER; PROTEIN; PROTEIN S100B; TAU PROTEIN; UNCLASSIFIED DRUG;

AGE; AGING; ALZHEIMER DISEASE; AMYLOID PLAQUE; ANTIBODY LABELING; ASTROCYTE; ASTROCYTOSIS; BLOOD BRAIN BARRIER; BRAIN ATROPHY; BRAIN CORTEX; CELL INTERACTION; CELL METABOLISM; CELL STRUCTURE; CYTOPATHOLOGY; DIFFUSE LEWY BODY DISEASE; DNA DAMAGE RESPONSE; FRONTOTEMPORAL DEMENTIA; GLIOSIS; GOLGI STAIN; GRAY MATTER; HUMAN; HYPERTROPHY; IMMUNOHISTOCHEMISTRY; INTRACELLULAR SIGNALING; MULTIINFARCT DEMENTIA; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROFIBRILLARY TANGLE; NEUROVASCULAR COUPLING; NEUROVASCULAR UNIT; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; STEM CELL; SUBVENTRICULAR ZONE; SYNAPSE; VASCULAR AMYLOIDOSIS; WHITE MATTER; ANIMAL; DEMENTIA; METABOLISM; PATHOLOGY;

AGING; ALZHEIMER DISEASE; ANIMALS; ASTROCYTES; DEMENTIA; HUMANS;

EID: 85019923681     PISSN: 03051846     EISSN: 13652990     Source Type: Journal    
DOI: 10.1111/nan.12338     Document Type: Review

References (156)

1. Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med 2009; 6: e1000180
2. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C. Age, neuropathology, and dementia. N Engl J Med 2009; 360: 2302–9
3. Wharton SB, Brayne C, Savva GM, Matthews FE, Forster G, Simpson J, Lace G, Ince PG. Epidemiological neuropathology: the MRC Cognitive Function and Aging Study experience. J Alzheimers Dis 2011; 25: 359–72
4. Fotuhi M, Hachinski V, Whitehouse PJ. Changing perspectives regarding late-life dementia. Nat Rev Neurol 2009; 5: 649–58
5. Boyle P, Wilson R, Yu L, Barr A, Honer W, Schneider J, Bennett D. Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol 2013; 74: 478–9
6. Bennett D, Schneider J, Arvanitakis Z, Kelly J, Aggarwal N, Shah R, Wilson R. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006; 66: 1837–44
7. Haroutunian V, Schnaider-Beeri M, Schmeidler J, Wysocki M, Purohit D, Perl D, Libow L, Lesser G, Maroukian M, Grossman HT. Role of the neuropathology of Alzheimer disease in dementia in the oldest old. Arch Neurol 2008; 65: 1211–17
8. Prohovnic I, Perl D, Davis K, Libow L, Lesser G, Haroutunian V. Dissociation of neuropathology from severity of dementia in late-onset Alzheimer's disease. Neurology 2006; 66: 49–55
9. Serrano-Pozo A, Qian J, Monsell S, Blacker D, Gomez-Isla T, Betensky R, Growdon J, Johnson K, Frosch M, Sperling R, Hyman B. Mild to moderate Alzheimer dementia with insufficient neuropathological changes. Ann Neurol 2014; 75: 597–601
10. Sagare A, Bell R, Zhao Z, Ma Q, Winkler E, Ramanathan A, Zlokovic B. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun 2013; 2: 2932
11. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011; 12: 723–38
12. Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of astrocytic form and function. Methods Mol Biol 2012; 814: 23–45
13. Kimelberg HK. Functions of mature mammalian astrocytes: a current view. Neuroscientist 2010; 16: 79–106
14. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 2002; 22: 183–92
15. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A. Glial cells in (patho)physiology. J Neurochem 2012; 121: 4–27
16. Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, Xu Q, Wyatt JD, Pilcher W, Ojemann JG, Ransom BR, Goldman SA, Nedergaard M. Uniquely hominid features of adult human astrocytes. J Neurosci 2009; 29: 3276–87
17. Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends Neurosci 2006; 29: 547–53
18. Sovrea AS, Bosca AB. Astrocytes reassessment – an evolving concept part one: embryology, biology, morphology and reactivity. J Mol Psychiatry 2013; 1: 18
19. Kessaris N, Pringle N, Richardson WD. Specification of CNS glia from neural stem cells in the embryonic neuroepithelium. Philos Trans R Soc Lond B Biol Sci 2008; 363: 71–85
20. Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 2004; 7: 1233–41
21. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999; 97: 703–16
22. Chaboub LS, Deneen B. Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev Neurosci 2012; 34: 379–88
23. Yang Z, Wang K. Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci 2015; 38: 364–74
24. Messing A, Brenner B, Feany M, Nedergaard M, Goldman J. Alexander Disease. J Neurosci 2012; 32: 5017–23
25. Morgan T, Rozovsky I, Goldsmith S, Stone D, Yoshida T, Finch C. Increased transcription of the astrocyte gene GFAP during middle-age is attenuated by food restriction: implications for the role of oxidative stress. Free Radic Biol Med 1997; 23: 524–8
26. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010; 119: 7–35
27. Verkhratsky A, Butt A. General Pathophysiology of Glia. Glial Neurobiology A Textbook Chichester, pp. 155–66. England: John Wiley and Sons, 2007
28. Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia 2005; 50: 427–34
29. Jing R, Wilhelmsson U, Goodwill W, Li L, Pan Y, Pekny M, Skalli O. Synemin is expressed in reactive astrocytes in neurotrauma and interacts differentially with vimentin and GFAP intermediate filament networks. J Cell Sci 2007; 120: 1267–77
30. Zamanian J, Xu L, Foo L, Nouri N, Zhou L, Giffard R, Barres B. Genomic analysis of reactive astrogliosis. J Neurosci 2012; 32: 6391–410
31. Howarth C. The contribution of astrocytes to the regulation of cerebral blood flow. Front Neurosci 2014; 8: doi: 10.3389/fnins.2014.00103. Article 103
32. Lecuyer M-A, Kebir H, Prat A. Glial influences on BBB functoins and molecular players in immune cell trafficking. Biochim Biophys Acta 2015; 1862(3): 472–82. doi: 10.1016/j.bbadis.2015.10.004 (in press)
33. Willis CL, Leach L, Clarke GJ, Nolan CC, Ray DE. Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia 2004; 48: 1–13
34. Willis CL, Nolan CC, Reith SN, Lister T, Prior MJ, Guerin CJ, Mavroudis G, Ray DE. Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 2004; 45: 325–37
35. Abbott N, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7: 41–53
36. Haber M, Zhou L, Murai KK. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J Neurosci 2006; 26: 8881–91
37. Nishida H, Okabe S. Direct astrocytic contacts regulate local maturation of dendritic spines. J Neurosci 2007; 27: 331–40
38. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science 2001; 291: 657–61
39. Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999; 22: 208–15
40. Auld DS, Robitaille R. Glial cells and neurotransmission: an inclusive view of synaptic function. Neuron 2003; 40: 389–400
41. Di CM, Chuquet J, Liaudet N, Bhaukaurally K, Santello M, Bouvier D, Tiret P, Volterra A. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat Neurosci 2011; 14: 1276–84
42. Nett WJ, Oloff SH, McCarthy KD. Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. J Neurophysiol 2002; 87: 528–37
43. Bezzi P, Volterra A. Imaging exocytosis and recycling of synaptic-like microvesicles in astrocytes. Cold Spring Harb Protoc 2014; doi:10.1101/pdb.prot081711
44. Parpura V, Verkhratsky A. Homeostatic function of astrocytes: Ca(2+) and Na(+) signalling. Translational neuroscience 2012; 3: 334–44
45. Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 2009; 32: 421–31
46. Schousboe A, Sarup A, Bak LK, Waagepetersen HS, Larsson OM. Role of astrocytic transport processes in glutamatergic and GABAergic neurotransmission. Neurochem Int 2004; 45: 521–7
47. Norenberg MD, Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 1979; 161: 303–10
48. Arnth-Jensen N, Jabaudon D, Scanziani M. Cooperation between independent hippocampal synapses is controlled by glutamate uptake. Nat Neurosci 2002; 5: 325–31
49. Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 2010; 11: 87–99
50. Gibbs M, Hutchinson D, Hertz L. Astrocytic involvement in learning and memory consolidation. Neurosci Biobehav Rev 2008; 32: 927–44
51. Belanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011; 14: 724–38
52. Newington JT, Harris RA, Cumming RC. Reevaluating Metabolism in Alzheimer's Disease from the Perspective of the Astrocyte-Neuron Lactate Shuttle Model. J Neurodegener Dis 2013; 2013: 234572
53. Muller MS. Functional impact of glycogen degradation on astrocytic signalling. Biochem Soc Trans 2014; 42: 1311–15
54. Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia 2007; 55: 1263–71
55. Allaman I, Belanger M, Magistretti P. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 2011; 34: 76–87
56. Pfrieger F, Ungerer N. Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 2011; 50: 357–71
57. Vives V, Alonso G, Solal AC, Joubert D, Legraverend C. Visualization of S100B-positive neurons and glia in the central nervous system of EGFP transgenic mice. J Comp Neurol 2003; 457: 404–19
58. Hachem S, Aguirre A, Vives V, Marks A, Gallo V, Legraverend C. Spatial and temporal expression of S100B in cells of oligodendrocyte lineage. Glia 2005; 51: 81–97
59. Steiner J, Bernstein HG, Bielau H, Berndt A, Brisch R, Mawrin C, Keilhoff G, Bogerts B. Evidence for a wide extra-astrocytic distribution of S100B in human brain. BMC Neurosci 2007; 8: 2
60. Lee A, Pow D. Astrocytes: glutamate transport and alternate splicing of transporters. Int J Biochem Cell Biol 2010; 42: 1901–6
61. Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Savva G, Brayne C, Wharton SB. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 2010; 31: 578–90
62. Fluteau A, Ince P, Minett T, Matthews F, Brayne C, Garwood C, Ratcliffe L, Morgan S, Heath P, Shaw P, Wharton S, Simpson J. The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain. Neurosci Lett 2015; 609: 11–17
63. Akiyama H, Tooyama I, Kawamata T, Ikeda K, McGeer P. Morphological diversities of CD44 positive astrocytes in the cerebral cortex of normal subjects and patients with Alzheimer's disease. Brain Res 1993; 632: 249–59
64. Cahoy J, Emery B, Kaushal A, Foo L, Zamanian J, Christopherson K, Xing Y, Lubisher J, Krieg P, Krupenko S, Thompson W, Barres B. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 2008; 28: 264–78
65. + astrocytes in vivo in astroglial reporter mice. Glia 2011; 59: 200–7
66. Flugge G, Araya-Callis C, Garea-Rodriguez E, Stadelmann-Nessler C, Fuchs E. NDRG2 as a marker protein for brain astrocytes. Cell Tissue Res 2014; 357: 31–41
67. Lin K, Yin A, Yao L, Li Y. N-myc downstream-regulated gene 2 in the nervous system: from expression pattern to function. Acta Biochim Biophys Sin 2015; 47: 761–6
68. Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G. The hallmarks of ageing. Cell 2013; 153: 1194–217
69. Sheng J, Mrak R, Rovnaghi C, Kozlowska E, Van Eldik L, Griffin W. Human brain S100β and S100β mRNA expression increases with age: pathogenic implications for Alzheimer's disease. Neurobiol Aging 1996; 17: 359–63
70. Wu Y, Zhang AQ, Yew DT. Age related changes of various markers of astrocytes in senescence-accelerated mice hippocampus. Neurochem Int 2005; 46: 565–74
71. Nichols N, Day J, Laping N, Johnson S, Finch C. GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 1993; 14: 421–9
72. Orre M, Kamphuis W, Osborn L, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol E. Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 2014; 35: 1–14
73. Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 2011; 34: 3–11
74. Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C. Astrocyte senescence as a component of Alzheimer's disease. PLoS ONE 2012; 7: e45069
75. Schultz C, Ghebremedhin E, del Tredici K, Rub U, Braak H. High prevalence of thorn-shaped astrocytes in the aged human medial temporal lobe. Neurobiol Aging 2004; 25: 397–405
76. Lace G, Ince P, Brayne C, Savva G, Matthews F, de Silva R, Simpson J, Wharton S. Mesial temporal astrocyte tau pathology in the MRC-CFAS ageing brain cohort. Dement Geriatr Cogn Disord 2012; 34: 15–24
77. Wharton S, Minett T, Drew D, Forster G, Matthews F, Brayne C, Ince P. Epidemiological pathology of tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe Protocol) to the MRC cognitive function and ageing brain study. Acta Neuropathol Commun; 4: 11.
78. Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H, Cairns NJ, Crary JF, Duyckaerts C, Ghetti B, Halliday GM, Ironside JW, Love S, Mackenzie IR, Munoz DG, Murray ME, Nelson PT, Takahashi H, Trojanowski JQ, Ansorge O, Arzberger T, Baborie A, Beach TG, Bieniek KF, Bigio EH, Bodi I, Dugger BN, Feany M, Gelpi E, Gentleman SM, Giaccone G, Hatanpaa KJ, Heale R, Hof PR, Hofer M, Hortobágyi T, Jellinger K, Jicha GA, Ince P, Kofler J, Kövari E, Kril JJ, Mann DM, Matej R, McKee AC, McLean C, Milenkovic I, Montine TJ, Murayama S, Lee EB, Rahimi J, Rodriguez RD, Rozemüller A, Schneider JA, Schultz C, Seeley W, Seilhean D, Smith C, Tagliavini F, Takao M, Thal DR, Toledo JB, Tolnay M, Troncoso JC, Vinters HV, Weis S, Wharton SB, White CL, Wisniewski T, Woulfe JM, Yamada M, Dickson DW. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 2016; 131: 87–102
79. Nicoll JA, Weller RO. A new role for astrocytes: beta-amyloid homeostasis and degradation. Trends Mol Med 2003; 9: 281–2
80. Chung WS, Welsh CA, Barres BA, Stevens B. Do glia drive synaptic and cognitive impairment in disease? Nat Neurosci 2015; 18: 1539–45
81. Wang L, Gutmann D, Roos R. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum Mol Genet 2011; 20: 286–93
82. Yamanaka K, Chun S, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann D, Takahashi R, Misawa H, Cleveland D. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neurosci 2008; 11: 251–3
83. Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ. Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 2011; 122: 657–71
84. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 2003; 9: 453–7
85. Thal DR, Schultz C, Dehghani F, Yamaguchi H, Braak H, Braak E. Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathol 2000; 100: 608–17
86. Funato H, Yoshimura M, Yamazaki T, Saido TC, Ito Y, Yokofujita J, Okeda R, Ihara Y. Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. Am J Pathol 1998; 152: 983–92
87. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J. Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 2004; 25: 663–74
88. Basak JM, Verghese PB, Yoon H, Kim J, Holtzman DM. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. J Biol Chem 2012; 287: 13959–71
89. Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 2009; 64: 632–44
90. Thal DR. The role of astrocytes in amyloid beta-protein toxicity and clearance. Exp Neurol 2012; 236: 1–5
91. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2011; 2: e167
92. Zhao J, O'Connor T, Vassar R. The contribution of activated astrocytes to Abeta production: implications for Alzheimer's disease pathogenesis. J Neuroinflammation 2011; 8: 150
93. Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer's disease. Lancet Neurol 2013; 12: 92–104
94. Jiang Q, Jin S, Jiang Y, Liao M, Feng R, Zhang L, Liu G, Hao J. Alzheimer's disease variants with genome-wide significance are significantly enriched in immune pathways and active in immune cells. Mol Neurobiol 2016; [Epub ahead of print]
95. Lambert J, Grenier-Boley B, Chouraki V, Heath S, Zelenika D, Fievet N, Hannequin D, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues J, Tzourio C, Campion D, Lathrop M, Amouyel P. Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis. J Alzheimers Dis 2010; 20: 1107–18
96. Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, Pocklington A, Abraham R, Hollingworth P, Sims R, Gerrish A, Pahwa JS, Jones N, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Peters O, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Rüther E, Carrasquillo MM, Pankratz VS, Younkin SG, Hardy J, O'Donovan MC, Owen MJ, Williams J. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 2010; 5: e13950
97. Heppner R, Ransohoff R, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 2015; 16: 358–72
98. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. Scientific World Journal 2012; 2012: 756357
99. Heneka MT, O'Banion MK, Terwel D, Kummer MP. Neuroinflammatory processes in Alzheimer's disease. J Neural Transm (Vienna) 2010; 117: 919–47
100. Phillips EC, Croft CL, Kurbatskaya K, O'Neill MJ, Hutton ML, Hanger DP, Garwood CJ, Noble W. Astrocytes and neuroinflammation in Alzheimer's disease. Biochem Soc Trans 2014; 42: 1321–5
101. Orre M, Kamphuis W, Osborn LM, Jansen AH, Kooijman L, Bossers K, Hol EM. Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol Aging 2014; 35: 2746–60
102. Shao W, Zhang S-Z, Tang M, Zhang X, Zhou Z, Yin Y, Zhou Q, Huang Y, Liu Y, Wawrousek E, Chen T, Li S-B, Xu M, Zhou J, Hu G, Zhou J. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via aB-crystallin. Nature 2013; 494: 90–4
103. Furman J, Sama D, Gant J, Beckett T, Murphy M, Bachstetter A, Van Eldick L, Norris C. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer's disease. J Neurosci 2012; 32: 16129–40
104. Vijayan VK, Geddes JW, Anderson KJ, Chang-Chui H, Ellis WG, Cotman CW. Astrocyte hypertrophy in the Alzheimer's disease hippocampal formation. Exp Neurol 1991; 112: 72–8
105. Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A. Astroglia in dementia and Alzheimer's disease. Cell Death Differ 2009; 16: 378–85
106. Stephan BCM, Wharton SB, Simpson J, Matthews FE, Ince P, Brayne C. The epidemiological neuropathology of dementia and the implications for drug development. Neurodegener Dis Manag 2012; 2: 471–82
107. Brayne C, Barker R, Grupe A, Harold D, Ince P, Savva G, Williams J, Williams-Gray C, Wharton S. From molecule to clinic and community for neurodegeneration: research to bridge translational gaps. J Alzheimers Dis 2012; 33 (Suppl 1): S385–96
108. Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs J, Jansen A, Verveer M, de Groot L, Smith V, Rangarajan S, Rodriquez J, Orre M, Hol E. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS ONE 2012; 7: e42823
109. Kamphuis W, Middeldorp J, Kooijman L, Sluijs J, Kooi E-J, Moeton M, Freriks M, Mizee M, Hol E. Glial fibrillary acidic protein isoform expression in plaque related astogliosis in Alzheimer's disease. Neurobiol Aging 2014; 35: 492–510
110. Nielsen A, Holm I, Johansen M, Bonven B, Jorgensen P, Jorgensen A. A new splice variant of glial fibrillary acidic protein, GFAPe, interacts with the presenilin proteins. J Biol Chem 2002; 277: 29983–91
111. Robel S, Sontheimer H. Glia as drivers of abnormal neuronal activity. Nat Neurosci 2016; 19: 28–33
112. Busche M, Grienberger C, Keskin A, Song B, Neumann U, Staufenbiel M, Forstl H, Konnerth A. Decreased amyloid-b and increased neuronal hyperactivity by immunotherapy in Alzheimer's models. Nat Neurosci 2015; 18: 1725–8
113. 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
114. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ. Astrocytes in Alzheimer's disease. Neurotherapeutics 2010; 7: 399–412
115. Garwood C, Faizullabhoy A, Wharton SB, Ince PG, Heath P, Shaw PJ, Baxter L, Gelsthorpe C, Forster G, Matthews FE, Brayne C, Simpson JE. Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 2013; 39(7): 788–99
116. Tomimoto H, Akiguchi I, Suenaga T, Nishimura M, Wakita H, Nakamura S, Kimura J. Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer's disease patients. Stroke 1996; 27: 2069–74
117. Simpson JE, Fernando M, Clark L, Ince P, Matthews F, Forster G, O'Brien J, Barber R, Kalaria R, Brayne C, Shaw P, Lewis C, Wharton S. White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol Appl Neurobiol 2007; 33: 410–19
118. Garwood CJ, Simpson JE, Al Mashhadi S, Axe C, Wilson S, Heath PR, Shaw PJ, Matthews FE, Brayne C, Ince PG, Wharton SB. DNA damage response and senescence in endothelial cells of human cerebral cortex and relation to Alzheimer's neuropathology progression: a population-based study in the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) cohort. Neuropathol Appl Neurobiol 2014; 40: 802–14
119. Simpson JE, Ince PG, Haynes LJ, Theaker R, Gelsthorpe C, Baxter L, Forster G, Lace GL, Shaw PJ, Matthews FE, Savva GM, Brayne C, Wharton SB. Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 2010; 36: 25–40
120. De La Monte S, Sohn Y, Ganju N, Wands J. p53 and CD95 associated apoptosis in neurodegenerative disease. Lab Invest 1998; 78: 401–11
121. Nunomura A, Tamaoki T, Motohashi N, Nakamura M, McKeel D, Tabaton M, Lee H-G, Smith M, Perry G, Zhu X. The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons. J Neuropathol Exp Neurol 2012; 71: 233–41
122. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj E, Jones P, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood C, Petersen R, Smith M. Oxidative damage is the earliest event in Alzheimer Disease. J Neuropathol Exp Neurol 2001; 60: 759–67
123. Lovell M, Soman S, Bradley M. Oxidatively modified nucleic acids in preclinical Alzheimer's disease (PCAD) brain. Mech Ageing Dev 2011; 132: 443–8
124. Venkateshappa C, Harish G, Mahadevan A, Srinivas Bharath M, Shankar S. Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: implications for neurodegeneration in Alzheimer's disease. Neurochem Res 2012; 37: 1601–14
125. Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Ageing Cell 2004; 3: 169–76
126. Butterfield D, Boyd-Kimball D. Amyloid β-peptide (1-42) contributes to the oxidative stress and neurodegeneration found in Alzheimer disease brain. Brain Pathol 2004; 14: 426–32
127. Kobayashi K, Hayashi M, Nakano H, Shimazaki M, Sugimori K, Koshino Y. Correlation between astrocyte apoptosis and Alzheimer changes in gray matter lesions in Alzheimer's disease. J Alzheimers Dis 2004; 6: 623–32
128. Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology 2010; 58: 561–8
129. Waller R, Woodroofe MN, Francese S, Heath PR, Wharton SB, Ince PG, Sharrack B, Simpson JE. Isolation of enriched glial populations from post-mortem human CNS material by immuno-laser capture microdissection. J Neurosci Methods 2012; 208(2): 108–13
130. Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ, Gelsthorpe C, Baxter L, Forster G, Matthews FE, Brayne C, Wharton SB. Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer's pathology and APOE genotype. Neurobiol Aging 2011; 32: 1795–807
131. Garwood CJ, Ratcliffe LE, Morgan SV, Simpson JE, Owens H, Vazquez-Villasenor I, Heath PR, Romero IA, Ince PG, Wharton SB. Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Molecular Brain 2015; 8: 51
132. Heni M, Hennige AM, Peter A, Siegel-Axel D, Ordelheide AM, Krebs N, Machicao F, Fritsche A, Haring HU, Staiger H. Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS ONE 2011; 6: e21594
133. Genis L, Davila D, Fernandez S, Pozo-Rodrigalvarez A, Martinez-Murillo R, Torres-Aleman I. Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury. F1000Research 2014; 3: 28
134. Fernandez A, Jimenez S, Mecha M, Davila D, Guaza C, Vitorica J, Torres-Aleman I. Regulation of the phosphatase calcineurin by insulin-like growth factor 1 unveils a key role of astrocytes in Alzheimer's pathology. Mol Psychiat 2012; 17: 705–18
135. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Investig 2012; 122: 1316–38
136. Bosco D, Fava A, Plastino M, Montalcini T, Pujia A. Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis. J Cell Mol Med 2011; 15: 1807–21
137. Picone P, Giacomazza D, Vetri V, Carrotta R, Militello V, San Biagio P, Di Carlo M. Insulin-activated Akt rescues Ab oxidative stress-induced cell death by orchestrating molecular trafficking. Ageing. Cell 2011; 10: 832–43
138. Zhao WQ, De Felice FF, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 2008; 22: 246–60
139. Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease. Am J Pathol 2011; 179: 1373–84
140. Mathur R, Ince PG, Minett T, Garwood CJ, Shaw PJ, Matthews FE, Brayne C, Simpson JE, Wharton SB. A reduced astrocyte response to beta-amyloid plaques in the ageing brain associates with cognitive impairment. PLoS ONE 2015; 10: e0118463
141. Kobayashi K, Hayashi M, Nakano H, Fukutani Y, Sasaki K, Shimazaki M, Koshino Y. Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer's disease. Neuropathol Appl Neurobiol 2002; 28: 238–51
142. Sjobeck M, Englund E. Glial levels determine severity of white matter disease in Alzheimer's disease: a neuropathological study of glial changes. Neuropathol Appl Neurobiol 2003; 29: 159–69
143. Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales K, Paul S. Apolipoprotein E promotes astrocyte colocalisation and degradation of deposited amyloid-β peptides. Nature Med 2004; 10: 719–26
144. Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P, Alafuzoff I. Astrogliosis and the ApoE genotype. An immunohistochemical study of postmortem human brain tissue. Dement Geriatr Cogn Disord 1999; 10: 252–7
145. Alafuzoff I, Overmyer M, Helisalmi S, Soininen H. Lower counts of astroglia and activated microglia in patients with Alzheimer's disease with regular use of non-steroidal anti-inflammatory drugs. J Alzheimers Dis 2000; 2: 37–46
146. Enciu AM, Constantinescu SN, Popescu LM, Muresanu DF, Popescu BO. Neurobiology of vascular dementia. J Aging Res 2011; 2011: 401604
147. Kimbrough I, Robel S, Roberson E, Sontheimer H. Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 2015; 138: 3716–33
148. Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol 2011; 122: 293–311
149. Hung VK, Yeung PK, Lai AK, Ho MC, Lo AC, Chan KC, Wu EX, Chung SS, Cheung CW, Chung SK. Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion. J Cereb Blood Flow Metab 2015; 35(10): 1687–96
150. Broe M, Kril J, Halliday GM. Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. Brain 2004; 10 (Pt 10): 2214–20
151. Martin JA, Craft DK, Su JH, Kim RC, Cotman CW. Astrocytes degenerate in frontotemporal dementia: possible relation to hypoperfusion. Neurobiol Aging 2001; 22: 195–207
152. Terada S, Ishizu H, Haraguchi T, Takehisa Y, Tanabe Y, Kawai K, Kuroda S. Tau-negative astrocytic star-like inclusions and coiled bodies in dementia with Lewy bodies. Acta Neuropathol 2000; 100: 464–8
153. Terada S, Ishizu H, Yokota O, Tsuchiya K, Nakashima H, Ishihara T, Fujita D, Ueda K, Ikeda K, Kuroda S. Glial involvement in diffuse Lewy body disease. Acta Neuropathol 2003; 105: 163–9
154. Kovacs G. Neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 2015; 41: 3–23
155. Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, Ditsworth D, Lagier-Tourenne C, Smith RA, Ravits J, Burghes AH, Shaw PJ, Cleveland DW, Kolb SJ, Kaspar BK. Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 2014; 111: 829–32
156. Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 2011; 29: 824–8