S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model.
Inflammation, insoluble protein deposition and neuronal cell loss are important features in the Alzheimer's disease (AD) brain. To investigate the regulatory genes responsible for the neuropathology in AD, we performed microarray analysis with APP(V717I)-CT100 transgenic mice, an animal model of AD, and isolated the S100a9 gene, which encodes an inflammation-associated calcium binding protein. In another AD animal model, Tg2576 mouse brain, and in human AD brain, induction of S100a9 was confirmed. The endogenous expression of S100a9 was induced by treatment with Abeta or CT peptides in a microglia cell line, BV2 cells. In these cells, silencing study of S100a9 showed that the induction of S100a9 increased the intracellular calcium level and up-regulated the inflammatory cytokines (IL-1beta and TNFalpha) and iNOS. S100a9 lentiviral short hairpin RNA (sh-S100a9) was injected into the hippocampus region of the brains of 13-month-old Tg2576 mice. At two months after injection, we found that knockdown of S100a9 expression had improved the cognition decline of Tg2576 mice in the water maze task, and had reduced amyloid plaque burden. These results suggest that S100a9 induced by Abeta or CT contributes to cause inflammation, which then affects the neuropathology including amyloid plaques burden and impairs cognitive function. Thus, the inhibition of S100a9 is a possible target for AD therapy.
Ha
Tae-Young
TY
Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea.
Chang
Keun-A
KA
Kim
Jeong a
Ja
Kim
Hye-Sun
HS
Kim
Seonghan
S
Chong
Young Hae
YH
Suh
Yoo-Hun
YH
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000523:psychology*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000502:physiology; D017931:DNA Primers; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D040502:Calgranulin B; D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators