Cover image for Vol. 63 Issue 4

Edited By: Bruce R. Ransom and Helmut Kettenmann

Impact Factor: 5.466

ISI Journal Citation Reports © Ranking: 2013: 35/252 (Neurosciences)

Online ISSN: 1098-1136

Virtual Issue: Involvement of glial cells in Alzheimer disease pathogenesis

Patrick L McGeer , Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada

Neuroscience over the past two decades has been dominated by discoveries concerning the functions of glia in brain. The journal GLIA was founded during this period and has been a major vehicle for publishing seminal advances in this rapidly expanding area. To trace these advances, and to help investigators build a solid foundation in this realm of neuroscience, the editors of GLIA are embarking on an entirely novel approach. That is to republish in web-only issues of the journal key papers that have appeared in GLIA. In that way, scientists can readily develop a solid background in selected topics that are particularly important to their field of endeavor.

The focus for this issue is Alzheimer disease. There are three reasons for such a choice. The first is that Alzheimer disease is one of the most important unsolved disorders of our time. The second is that glial cells are now known to play an important role in its pathology. The third is that many of the glial cell reactions that are observed in Alzheimer disease have application in other neurodegenerative pathologies.

It would be difficult to overestimate the urgency for progress in the field of Alzheimer disease. In the World Alzheimer Report 2010 ( it is estimated that thirty five million people are affected worldwide at a current cost of $604 billion per year. The incidence is about twenty thousand new cases per day. With baby boomers now entering the age of risk, these figures are projected to escalate rapidly in the years to come. There are currently no approved drugs which modify the disease pathology, and unless such drugs are discovered and brought to the bedside, public health plans may find themselves in severe financial jeopardy.

Alzheimer disease has a special place in glial cell history because it was studies of post mortem Alzheimer brain tissue that opened up the field of neuroinflammation. Reactive microglia that were positive for the immune cell marker HLA-DR were identified phagocytosing senile plaque material (McGeer et al. 1987; Rogers et al. 1988). Prior to this time it was believed that neuroinflammation required engagement of the adaptive immune system and invasion of the brain by lymphocytes and monocytes. These studies not only demonstrated a neuroinflammatory reaction in a disease where none was believed to exist, but also vindicated the work of Hortega (Hortega 1919) that microglia were phagocytes of mesodermal origin, which had been disputed for more than six decades, Similar findings were soon demonstrated in other neurodegenerative diseases of aging, indicating the generality of a neuroinflammatory response. The field quickly expanded to the point where in academia there are now Departments and Professors of Neuroinflammation.

In this issue, it is not possible to do justice to the many excellent papers on the subject that have appeared in GLIA. The papers reproduced here are only a sampling, admittedly arbitrary, which offer no more than a flavor of the field. Papers are selected, often highly cited, from each year of publication from 1993 to 2010. A further list of all papers dealing with Alzheimer disease that are not reproduced in this issue is provided as an appendix, so that a comprehensive view of GLIA contributions is available

The papers reproduced here commenced with an issue in Volume 7 which was dedicated to microglial activation. They then trace, in a limited, time-dependent sense, evolution in the field.

The groundwork for this issue was laid by four key papers from the 1993 special issue on microglia. They are by Ling and Wong describing the origin and nature of microglia; Dickson et al. detailing cytokines and microglia in Alzheimer disease and Aids; Banati et al. on the cytotoxicity of microglia; and McGeer et al. on microglia in neurodegenerative diseases generally.

This was followed in 1994 by a paper by Lee et al. on GM-CSF bringing about proliferation of microglia in culture. This explained one mechanism by which microglia could be replenished in living brain. Banati et al. in 1995 described how an inflammatory reaction in EAE causes microglia to express APP, the precursor of beta- amyloid protein. Fiebich et al. in 1996 showed that cyclooxygenase-2 expression in microglia was induced by adenosine A2 receptors. Bechmann and Nitsch in 1997, and Minn et al. in 1998 cast light on astrocytic functions by showing that they incorporate degenerating fibers and can upregulate GFAP. Akiyama et al. in 1999 showed that beta-amyloid protein was found in glial cells in Alzheimer disease, while Stephenson et al. showed that phospholipase A2 is induced in reactive glia in neurodegeneration.

Cardinaux et al. began the new century with a paper on inflammatory cytokines inducing transcription factors in astrocytes. Lue et al. followed up in 2001 with a paper on the repertoire of inflammatory microglia in Alzheimer disease and controls. In 2002, Rogers et al. then described the clearance of beta-amyloid protein. Hartlage-Rubsamen et al. in 2003 showed that BACE, the enzyme controlling the obligatory first step in A-beta synthesis, was stimulant dependent in astrocytes.

In that year, Hosokawa et al. focused on oligodendroglial cells, showing that they expressed the RNAs and proteins of the complement system. Oligodendroglia were named by Hortega as the component of his “el tercer elemento” that were difficult to impregnate with his ammoniacal silver nitrate stain (Hortega. 1919). He recognized that they were of epithelial origin, and not of mesodermal origin as were microglia, the other component of “el tercer elemento”. Their role in Alzheimer disease has not been fully explored, but there is an unexplained phenomenon by which those areas of brain which are last to myelinate, are the first to degenerate (Braak and Braak 1996)

Xie et al. in 2004 showed that activated glia can induce neuron death via signaling pathways involving JNK and p38, while Ryu et al. showed that minocycline can inhibit neuronal death in rat hippocampus and glial activation induced by beta-amyloid peptide.

In 2005, Zhang et al. drew attention again to oligodendroglia by showing that cytokine toxicity to their precursors is mediated by iron. In 2006, Craft et al. showed that human amyloid beta-induced neuroinflammation is an early event in neurodegeneration. One possible route is described by Skaper et al. who showed that P2X(7) receptors on microglial cells mediate injury to cortical neurons in vitro. Herber et al. described microglial responses after intrahippocampal administration of the powerful inflammatory stimulant lipopolysaccharide and Seabrook et al. described the protective effects of minocycline in transgenic mice.

In 2007, Trapp et al described the role of microglia in synaptic stripping. In 2008, Wang et al. showed that long-chain ceramide is elevated in presenilin 1 transgenic mice and induces apoptosis in astrocytes.

Some important papers appeared in 2009 and 2010. In 2009, Pocivavsek et al drew attention to low-density lipoprotein receptors that regulate microglial inflammation through C-Jun-N-terminal kinase. Desai et al. reported that a triple-transgenic mouse model of Alzheimer disease showed abnormalities in brain myelination prior to the appearance of amyloid and tau pathology. Pan et al. found that tripchlorolide protected neuronal cells from microglial attack by inhibiting inflammatory induction via NF-kappa B and JNK. Szaingurten-Solodkin et al. reported on the regulatory role phospholipase A2 alpha in governing the NADPH oxidase activity and nitric oxide synthase induction in microglia.

In 2010, Mori et al. showed that over expression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg 2576 mouse model of Alzheimer disease. Lee et al. showed that hydrogen sulfide-releasing agents attenuated induction of neuroinflammation by activated microglia and astrocytes while Malm et al described the role and therapeutic potential of monocytic cells in Alzheimer disease.

The papers selected for reprinting in this issue are far from inclusive. There are many important papers in GLIA that are listed only in the appendix. However the reprinted papers do give a sense of the techniques that have been employed to build a broader understanding of glial function. They include post mortem studies of diseased brain tissue, in vitro culture of glial cells, in vivo testing of inflammatory agents, and administration of candidate drugs to Alzheimer disease transgenic mouse models. They represent only a beginning to a much richer future. A momentum is clearly building, and we can anticipate many important discoveries in future issues of GLIA.

Acknowledgement: This work was supported by the Pacific Alzheimer Research Foundation

E. A. Ling and W. C. Wong. The Origin and Nature of Ramified and Ameboid Microglia - A Historical Review and Current Concepts. Glia 7 (1):9-18, 1993.

D. W. Dickson, S. C. Lee, L. A. Mattiace, S. H. C. Yen, and C. Brosnan. Microglia and Cytokines in Neurological Disease, with Special Reference to Aids and Alzheimers-Disease. Glia 7 (1):75-83, 1993.

R. B. Banati, J. Gehrmann, P. Schubert, and G. W. Kreutzberg. Cytotoxicity of Microglia. Glia 7 (1):111-118, 1993.

P. L. McGeer, T. Kawamata, D. G. Walker, H. Akiyama, I. Tooyama, and E. G. McGeer. Microglia in Degenerative Neurological Disease. Glia 7 (1):84-92, 1993.

S. C. Lee, W. Liu, C. F. Brosnan, and D. W. Dickson. Gm-Csf Promotes Proliferation of Human Fetal and Adult Microglia in Primary Cultures. Glia 12 (4):309-318, 1994.

R. B. Banati, J. Gehrmann, J. Lannesvieira, H. Wekerle, and G. W. Kreutzberg. Inflammatory Reaction in Experimental Autoimmune Encephalomyelitis (Eae) Is Accompanied by A Microglial Expression of the Beta-A4-Amyloid Precursor Protein (App). Glia 14 (3):209-215, 1995.

B. L. Fiebich, K. Biber, K. Lieb, D. vanCalker, M. Berger, J. Bauer, and P. J. GebickeHaerter. Cyclooxygenase-2 expression in rat microglia is induced by adenosine A(2a)-receptors. Glia 18 (2):152-160, 1996.

Bechmann and R. Nitsch. Astrocytes and microglial cells incorporate degenerating fibers following entorhinal lesion: A light, confocal, and electron microscopical study using a phagocytosis-dependent labeling technique. Glia 20 (2):145-154, 1997.

A. Minn, M. Schubert, W. F. Neiss, and B. Muller-Hill. Enhanced GFAP expression in astrocytes of transgenic mice expressing the human brain-specific trypsinogen IV. Glia 22 (4):338-347, 1998.

H. Akiyama, H. Mori, T. Saido, H. Kondo, K. Ikeda, and P. L. McGeer. Occurrence of the diffuse amyloid beta-protein (A beta) deposits with numerous A beta-containing glial cells in the cerebral cortex of patients with Alzheimer's disease. Glia 25 (4):324-331, 1999.

D. Stephenson, K. Rash, B. Smalstig, E. Roberts, E. Johnstone, J. Sharp, J. Panetta, S. Little, R. Kramer, and J. Clemens. Cytosolic phospholipase A(2) is induced in reactive glia following different forms of neurodegeneration. Glia 27 (2):110-128, 1999.

J. R. Cardinaux, I. Allaman, and P. J. Magistretti. Pro-inflammatory cytokines induce the transcription factors C/EBP beta and C/EBP delta in astrocytes. Glia 29 (1):91-97, 2000.

L. F. Lue, R. Rydel, E. F. Brigham, L. B. Yang, H. Hampel, G. M. Murphy, L. Brachova, S. D. Yan, D. G. Walker, Y. Shen, and J. Rogers. Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia 35 (1):72-79, 2001.

J. Rogers, R. Strohmeyer, C. J. Kovelowski, and R. Li. Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40 (2):260-269, 2002.

M. Hartlage-Rubsamen, U. Zeitschel, J. Apelt, U. Gartner, H. Franke, T. Stahl, A. Gunther, R. Schliebs, M. Penkowa, V. Bigl, and S. Rossner. Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent. Glia 41 (2):169-179, 2003.

M. Hosokawa, A. Klegeris, J. Maguire, and P. L. McGeer. Expression of complement messenger RNAs and proteins by human oligodendroglial cells. Glia 42 (4):417-423, 2003.

Z. Xie, C. J. Smith, and L. J. Van Eldik. Activated glia induce neuron death via NLAP kinase signaling pathways involving JNK and p38. Glia 45 (2):170-179, 2004.

J. K. Ryu, S. Franciosi, P. Sattayaprasert, S. U. Kim, and J. G. McLarnon. Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 48 (1):85-90, 2004.

X. S. Zhang, M. Haaf, B. Todorich, E. Grosstephan, H. Schieremberg, N. Surguladze, and J. R. Connor. Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia 52 (3):199-208, 2005.

J. M. Craft, D. M. Watterson, and L. J. Van Eldik. Human amyloid beta-induced neuroinflammation is an early event in neurodegeneration. Glia 53 (5):484-490, 2006.

S. D. Skaper, L. Facci, A. A. Culbert, N. A. Evans, I. Chessell, J. B. Davis, and J. C. Richardson. P2X(7) receptors on microglial cells mediate injury to cortical neurons in vitro. Glia 54 (3):234-242, 2006.

D. L. Herber, J. L. Maloney, L. M. Roth, M. J. Freeman, D. Morgan, and M. N. Gordon. Diverse microglial responses after intrahippocampal administration of lipopolysaccharide. Glia 53 (4):382-391, 2006.

T. J. Seabrook, L. Y. Jiang, M. Maier, and C. A. Lemere. Minocycline affects microglia activation, A beta deposition, and behavior in APP-tg mice. Glia 53 (7):776-782, 2006.

Trapp BD, Wujek JR, Criste GA, et al. Evidence for synaptic stripping by cortical microglia GLIA 55 (4) 360-368, 2007

Wang G, Silva J, Dasgupta S, et al. Long-chain ceramide is elevated in presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes GLIA 56 (4), 449-456 2008.

Pocivavsek A, Burns MP, Rebeck GW .Low-Density Lipoprotein Receptors Regulate Microglial Inflammation Through C-Jun N-Terminal Kinase GLIA 57(4) 444-453, 2009.

Desai, M. K., K. L. Sudol, et al. (2009). Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 57(1): 54-65.

Pan, X. D., X. C. Chen, et al. (2009). Tripchlorolide protects neuronal cells from microglia-mediated beta-amyloid neurotoxicity through inhibiting NF-kappaB and JNK signaling. Glia 57(11): 1227-1238.

Szaingurten-Solodkin, I., N. Hadad, et al. (2009). Regulatory role of cytosolic phospholipase A2alpha in NADPH oxidase activity and in inducible nitric oxide synthase induction by aggregated Abeta1-42 in microglia. Glia 57(16): 1727-1740.

T Mori, N Koyama, GW Arendash, Y Horikoshi-Sakuraba, J Tan, T Town. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia 58 (3) 300-314, 2010.

Malm, T., M. Koistinaho, et al. (2010). The role and therapeutic potential of monocytic cells in Alzheimer's disease. Glia 58(8): 889-900.

Lee, M., A. Sparatore, et al. (2010). Hydrogen sulfide-releasing NSAIDs attenuate neuroinflammation induced by microglial and astrocytic activation. Glia 58(1): 103-113.


Braak H, Braak E 1996. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol. 92(2), 197-201.

Hortega P del Rio 1919. El “tercer elemento” de los centros nerviosis. Biol Soc Esp 9, 154-166.

McGeer PL, Itagaki S,Tago H, McGeer EG 1987. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neuroscience Letters 79, 195-2000.

Rogers J, Luber-Narod J, Styren SD, Civin WH, 1988. Expression of immune-system associated antigen by cells of the human central nervous system. Neurobiol Aging 9, 339-349.

Appendix: Other GLIA articles related to Alzheimer’s disease

Allaman, I., L. Pellerin, et al. (2000). "Protein targeting to glycogen mRNA expression is stimulated by noradrenaline in mouse cortical astrocytes." Glia 30(4): 382-391.

Bambrick, L. L., V. A. Golovina, et al. (1997). "Abnormal calcium homeostasis in astrocytes from the trisomy 16 mouse." Glia 19(4): 352-358.

Banati, R. B., J. Gehrmann, et al. (1993). "Early and rapid de novo synthesis of Alzheimer beta A4-amyloid precursor protein (APP) in activated microglia." Glia 9(3): 199-210.

Banati, R. B., G. Rothe, et al. (1993). "Detection of lysosomal cysteine proteinases in microglia: flow cytometric measurement and histochemical localization of cathepsin B and L." Glia 7(2): 183-191.

Beach, T. G., R. Walker, et al. (1989). "Patterns of gliosis in Alzheimer's disease and aging cerebrum." Glia 2(6): 420-436.

Bialowas-McGoey, L. A., A. Lesicka, et al. (2008). "Vitamin E increases S100B-mediated microglial activation in an S100B-overexpressing mouse model of pathological aging." Glia 56(16): 1780-1790.

Cho, H. J., S. K. Kim, et al. (2007). "IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes." Glia 55(3): 253-262.

Dekroon, R. M. and P. J. Armati (2001). "Synthesis and processing of apolipoprotein E in human brain cultures." Glia 33(4): 298-305.

Delgado, M., N. Varela, et al. (2008). "Vasoactive intestinal peptide protects against beta-amyloid-induced neurodegeneration by inhibiting microglia activation at multiple levels." Glia 56(10): 1091-1103.

Desai, M. K., B. J. Guercio, et al. (2011). "An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction." Glia 59(4): 627-640.

Dheen, S. T., Y. Jun, et al. (2005). "Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia." Glia 50(1): 21-31.

Eikelenboom, P., C. Bate, et al. (2002). "Neuroinflammation in Alzheimer's disease and prion disease." Glia 40(2): 232-239.

Familian, A., R. S. Boshuizen, et al. (2006). "Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation." Glia 53(3): 233-240.

Frank, S., G. J. Burbach, et al. (2008). "TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice." Glia 56(13): 1438-1447.

Gavillet, M., I. Allaman, et al. (2008). "Modulation of astrocytic metabolic phenotype by proinflammatory cytokines." Glia 56(9): 975-989.

Halleskog, C., J. Mulder, et al. (2011). "WNT signaling in activated microglia is proinflammatory." Glia 59(1): 119-131.

Hashioka, S., A. Klegeris, et al. (2011). "Proton pump inhibitors reduce interferon-gamma-induced

Huang, G., M. Dragan, et al. (2005). "Activation of catechol-O-methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons." Glia 51(1): 47-55.

Hughes, M. M., R. H. Field, et al. (2010). "Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrPSc, even upon LPS stimulation." Glia 58(16): 2017-2030.

Husemann, J., J. D. Loike, et al. (2002). "Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system." Glia 40(2): 195-205.

Klegeris, A. and P. L. McGeer (2005). "Chymotrypsin-like proteases contribute to human monocytic THP-1 cell as well as human microglial neurotoxicity." Glia 51(1): 56-64.

Kodam, A., M. Maulik, et al. (2010). "Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains." Glia 58(11): 1267-1281.

Koistinaho, M. and J. Koistinaho (2002). "Role of p38 and p44/42 mitogen-activated protein kinases in microglia." Glia 40(2): 175-183.

Lee, S. C., W. Liu, et al. (1994). "GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures." Glia 12(4): 309-318.

Lopes, K. O., D. L. Sparks, et al. (2008). "Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity." Glia 56(10): 1048-1060.

Malchiodi-Albedi, F., M. R. Domenici, et al. (2001). "Astrocytes contribute to neuronal impairment in beta A toxicity increasing apoptosis in rat hippocampal neurons." Glia 34(1): 68-72.

Malm, T. M., J. Magga, et al. (2008). "Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease." Glia 56(16): 1767-1779.

Melton, L. M., A. B. Keith, et al. (2003). "Chronic glial activation, neurodegeneration, and APP immunoreactive deposits following acute administration of double-stranded RNA." Glia 44(1): 1-12.

Miller, J. D., J. Cummings, et al. (1997). "Localization of perlecan (or a perlecan-related macromolecule) to isolated microglia in vitro and to microglia/macrophages following infusion of beta-amyloid protein into rodent hippocampus." Glia 21(2): 228-243.

Nadler, Y., A. Alexandrovich, et al. (2008). "Increased expression of the gamma-secretase components presenilin-1 and nicastrin in activated astrocytes and microglia following traumatic brain injury." Glia 56(5): 552-567.

Namba, T., M. Maekawa, et al. (2009). "The Alzheimer's disease drug memantine increases the number of radial glia-like progenitor cells in adult hippocampus." Glia 57(10): 1082-1090.

Natarajan, C., S. Sriram, et al. (2004). "Signaling through JAK2-STAT5 pathway is essential for IL-3-induced activation of microglia." Glia 45(2): 188-196.

Neumann, H. (2001). "Control of glial immune function by neurons." Glia 36(2): 191-199.

Nielsen, H. M., S. D. Mulder, et al. (2010). "Astrocytic A beta 1-42 uptake is determined by A beta-aggregation state and the presence of amyloid-associated proteins." Glia 58(10): 1235-1246.

Nielsen, H. M., R. Veerhuis, et al. (2009). "Binding and uptake of A beta1-42 by primary human astrocytes in vitro." Glia 57(9): 978-988.

Olabarria, M., H. N. Noristani, et al. (2010). "Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease." Glia 58(7): 831-838.

Paradisi, S., B. Sacchetti, et al. (2004). "Astrocyte modulation of in vitro beta-amyloid neurotoxicity." Glia 46(3): 252-260.

Park, J. Y., S. R. Paik, et al. (2008). "Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson's disease." Glia 56(11): 1215-1223.

Pereira, H. A., X. Ruan, et al. (2003). "Activation of microglia: a neuroinflammatory role for CAP37." Glia 41(1): 64-72.

Pihlaja, R., J. Koistinaho, et al. (2008). "Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease." Glia 56(2): 154-163.

Postler, E., A. Lehr, et al. (1997). "Expression of the S-100 proteins MRP-8 and -14 in ischemic brain lesions." Glia 19(1): 27-34.

Schipper, H. M. and S. Cisse (1995). "Mitochondrial constituents of corpora amylacea and autofluorescent astrocytic inclusions in senescent human brain." Glia 14(1): 55-64.

Streit, W. J. (2002). "Microglia as neuroprotective, immunocompetent cells of the CNS." Glia 40(2): 133-139.

Teaktong, T., A. Graham, et al. (2003). "Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes." Glia 41(2): 207-211.

Tilgner, J., B. Volk, et al. (2001). "Continuous interleukin-6 application in vivo via macroencapsulation of interleukin-6-expressing COS-7 cells induces massive gliosis." Glia 35(3): 234-245.

Viviani, B., E. Corsini, et al. (2000). "Dying neural cells activate glia through the release of a protease product." Glia 32(1): 84-90.