Transgenic AD model mice, effects of potential anti-AD treatments on inflammation, and pathology.
The deposition of amyloid-β (Aβ) peptides in plaques and intracellular neurofibrillary tangles are the two main characteristic pathological features of Alzheimer's disease (AD). Significantly, plaques are surrounded by activated astrocytes, microglia, and possibly, macrophages, and it has been suggested that this activity contributes to the pathology. Whether this will lead to a decrease or an increase in the amount of Aβ deposition is not clear. To investigate the relation between amyloid neuropathology and inflammation, we examined the changes in amyloid pathology in the hippocampus and neocortex following three anti-inflammatory treatments aimed at reducing the amyloid burden. In these studies we treated mice with different non-steroidal anti-inflammatory drugs for several months (i.e., from 8 through 14 months of age), and studied the Aβ pathology and inflammation in the brain. Sham treatment and flurbiprofen treatment did not affect Aβ pathology, and a low dose HCT 1026 (10 mg/kg; a nitric oxide-donating flurbiprofen analog that has additional useful properties, including a remarkable gastrointestinal safety) did not affect pathology either, however a higher dose of HCT 1026 (30 mg/kg) did reduce the Aβ load. Furthermore, this treatment reduced the amount of microglial activation surrounding plaques. In contrast, the low dose of HCT 1026 increased GFAP activation, but did not change microglial activation. Together the data indicate that changing the activity of glial cells can lead to both a decrease of the amyloid burden, and to detrimental changes, likely caused by the interplay between the activation levels of astrocytes and microglial cells.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
Thomas
T
van Groen
Pasi
P
Miettinen
Inga
I
Kadish
D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000187:drug effects / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology*; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; C508853:PSEN1 protein, human; D053764:Presenilin-1; C036763:monocyte-macrophage differentiation antigen; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D017493:Leukocyte Common Antigens