Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice.
Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid-beta protein in the aged brain. Inefficient clearance of amyloid-beta from brain tissue is believed to play a major role in the pathogenesis of these deposits. Since amyloid-beta clearance likely involves activation of microglial cells via toll-like receptors and since these receptors and their signaling pathways are regarded as potential therapeutic targets, we have studied the expression of toll-like receptor (tlr) mRNAs in an animal model of AD (APP23 transgenic mice). Laser microdissection was used to harvest plaques, tissue surrounding plaques and plaque-free tissue from cortex of aged APP23 transgenic mice and age-matched controls. Real-time RT-PCR was employed to quantify expression levels of different tlr mRNAs in these tissues. This revealed a strong upregulation of tlr2, tlr4, tlr5, tlr7 and tlr9 mRNAs in plaque material compared to plaque-free tissue. In contrast, tlr3 was not significantly upregulated. Plaque-free tissue did not show an increased expression of any tlr mRNAs compared to age-matched control mice. Double-immunofluorescence for TLR2 and the microglial marker Iba1 was used to demonstrate localization of TLR2 on plaque-associated microglia. Taken together, these data show a strong upregulation of mRNAs encoding surface TLRs in plaque-associated brain tissue of aged APP23 transgenic mice. Since TLR-upregulation is restricted to plaques, modifying TLR-signaling may be a promising therapeutic strategy for plaque removal.
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Stefanie
S
Frank
Ekaterini
E
Copanaki
Guido J
GJ
Burbach
Ulrike C
UC
Müller
Thomas
T
Deller
D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000502:physiology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors