Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases

被引:70
作者
Walker, DG [1 ]
Lue, LF [1 ]
机构
[1] Sun Hlth Res Inst, Lab Neuroinflammat, Sun City, AZ 85351 USA
关键词
neurodegeneration; inflammation; phagocytosis; tissue culture;
D O I
10.1002/jnr.20484
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Inflammation-mediated mechanisms for human neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have evolved from being on the fringe of medical hypotheses to mainstream thinking. Pioneering immunopathology studies with human brain tissues identified microglia associated with neuropathologic hallmarks of these diseases. As activated macrophages were known to produce many potential toxic products, this gave rise to the hypothesis that activated microglia (brain resident macrophages) could be contributing to the degeneration of key target neurons in these diseases, as well as potential vascular dysfunction. Studies with microglia derived from different sources, including human brains, have confirmed that activated microglia can mediate neuronal cell death. Based on these theories, a number of human clinical trials with anti-inflammatory agents have been carried out on AD patients. Results to date have indicated a lack of effectiveness at slowing disease progression and have begun to cast doubt on the significance of inflammation in AD. It has been shown recently that activating microglia through immunization of amyloid plaque-developing mice with amyloid beta peptide (A beta) has promise as a therapeutic strategy and despite some setbacks, has potential as a treatment for AD patients. This article will consider experimental data with microglia to determine whether the additional targets need to be investigated. The use of human microglia cultures, in particular those derived from elderly diseased human brains, offers an experimental system that can closely model the cell type activated in human neuroclegenerative diseases. Experimental data produced by our laboratory and others is reviewed to determine the contribution of this unique experimental model to understanding disease mechanisms and possibly discovering new therapeutic targets. (c) 2005 Wiley-Liss, Inc.
引用
收藏
页码:412 / 425
页数:14
相关论文
共 170 条
[1]   Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression - A randomized controlled trial [J].
Aisen, PS ;
Schafer, KA ;
Grundman, M ;
Pfeiffer, E ;
Sano, M ;
Davis, KL ;
Farlow, MR ;
Jin, S ;
Thomas, RG ;
Thal, LJ .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2003, 289 (21) :2819-2826
[2]  
Akiyama H, 1999, GLIA, V25, P324, DOI 10.1002/(SICI)1098-1136(19990215)25:4<324::AID-GLIA2>3.0.CO
[3]  
2-5
[4]   IMMUNOHISTOCHEMICAL LOCALIZATION OF VITRONECTIN, ITS RECEPTOR AND BETA-3 INTEGRIN IN ALZHEIMER BRAIN-TISSUE [J].
AKIYAMA, H ;
KAWAMATA, T ;
DEDHAR, S ;
MCGEER, PL .
JOURNAL OF NEUROIMMUNOLOGY, 1991, 32 (01) :19-28
[5]   Granules in glial cells of patients with Alzheimer's disease are immunopositive for C-terminal sequences of beta-amyloid protein [J].
Akiyama, H ;
Schwab, C ;
Kondo, H ;
Mori, H ;
Kametani, F ;
Ikeda, K ;
McGeer, PL .
NEUROSCIENCE LETTERS, 1996, 206 (2-3) :169-172
[6]   Inflammation and Alzheimer's disease [J].
Akiyama, H ;
Barger, S ;
Barnum, S ;
Bradt, B ;
Bauer, J ;
Cole, GM ;
Cooper, NR ;
Eikelenboom, P ;
Emmerling, M ;
Fiebich, BL ;
Finch, CE ;
Frautschy, S ;
Griffin, WST ;
Hampel, H ;
Hull, M ;
Landreth, G ;
Lue, LF ;
Mrak, R ;
Mackenzie, IR ;
McGeer, PL ;
O'Banion, MK ;
Pachter, J ;
Pasinetti, G ;
Plata-Salaman, C ;
Rogers, J ;
Rydel, R ;
Shen, Y ;
Streit, W ;
Strohmeyer, R ;
Tooyoma, I ;
Van Muiswinkel, FL ;
Veerhuis, R ;
Walker, D ;
Webster, S ;
Wegrzyniak, B ;
Wenk, G ;
Wyss-Coray, T .
NEUROBIOLOGY OF AGING, 2000, 21 (03) :383-421
[7]   DO NONSTEROIDAL ANTIINFLAMMATORY DRUGS DECREASE THE RISK FOR ALZHEIMERS-DISEASE - THE ROTTERDAM STUDY [J].
ANDERSEN, K ;
LAUNER, LJ ;
OTT, A ;
HOES, AW ;
BRETELER, MMB ;
HOFMAN, A .
NEUROLOGY, 1995, 45 (08) :1441-1445
[8]   CD200 and membrane protein E interactions in the control of myeloid cells [J].
Barclay, AN ;
Wright, GJ ;
Brooke, G ;
Brown, MH .
TRENDS IN IMMUNOLOGY, 2002, 23 (06) :285-290
[9]   Oral valdecoxib and injected parecoxib for acute postoperative pain: A quantitative systematic review [J].
Jodie Barden ;
Jayne E Edwards ;
Henry J McQuay ;
R Andrew Moore .
BMC Anesthesiology, 3 (1)
[10]  
Becher B, 1996, J NEUROSCI RES, V45, P375