Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis.
The major pathological hallmark of amyloid diseases is the presence of extracellular amyloid deposits. Serum amyloid A (SAA) is an apolipoprotein primarily produced in the liver. Serum protein levels can increase one thousandfold after inflammation. SAA is the precursor to the amyloid A protein found in deposits of systemic amyloid A amyloid (AA or reactive amyloid) in both mouse and human. To study the factors necessary for cerebral amyloid formation, we have created a transgenic mouse that expresses the amyloidogenic mouse Saa1 protein in the brain. Using the synapsin promoter to drive expression of the Saa1 gene, the brains of transgenic mice expressed both RNA and protein. Under noninflammatory conditions, transgenic mice do not develop AA amyloid deposits in the brain; however, induction of a systemic acute-phase response in transgenic mice enhanced amyloid deposition. This deposition was preceded by an increase in cytokine levels in the brain, suggesting that systemic inflammation may be a contributing factor to the development of cerebral amyloid. The nonsteroidal anti-inflammatory agent indomethacin reduced inflammation and protected against the deposition of AA amyloid in the brain. These studies indicate that inflammation plays an important role in the process of amyloid deposition, and inhibition of inflammatory cascades may attenuate amyloidogenic processes, such as Alzheimer's disease.
Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
Jun-Tao
JT
Guo
Jin
J
Yu
David
D
Grass
Frederick C
FC
de Beer
Mark S
MS
Kindy
D000367:Age Factors; D000686:Amyloidosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D016704:Synapsins / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; D016704:Synapsins; D007213:Indomethacin