Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation.
beta-amyloid (A beta), derived form the beta-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A beta plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8- and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.
Koistinaho
Milla
M
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland.
Kettunen
Mikko I
MI
Goldsteins
Gundars
G
Keinänen
Riitta
R
Salminen
Antero
A
Ort
Michael
M
Bures
Jan
J
Liu
David
D
Kauppinen
Risto A
RA
Higgins
Linda S
LS
Koistinaho
Jari
J
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002245:Carbon Dioxide / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D016564:Amyloid beta-Protein Precursor; D001241:Aspirin; D002245:Carbon Dioxide; D004791:Enzyme Inhibitors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C514526:indole-5-carboxamide