S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model

• Published in: PloS one Vol. 5; no. 1; p. e8840
• Main Authors: Ha, Tae-Young, Chang, Keun-A, Kim, Jeong a, Kim, Hye-Sun, Kim, Seonghan, Chong, Young Hae, Suh, Yoo-Hun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.01.2010; Public Library of Science (PLoS)
• Subjects: Advertising executives; Age; Aged; Aged, 80 and over; Aging; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - psychology; Alzheimer's disease; Alzheimers disease; Analysis; Animal cognition; Animal genetic engineering; Animals; Base Sequence; Brain; Brain - metabolism; Brain research; Calcium; Calcium (intracellular); Calcium-binding protein; Calgranulin B - genetics; Calgranulin B - physiology; Cell adhesion & migration; Cell Line, Transformed; Cognition; Cognitive ability; Cytokines; Cytokines - physiology; Dementia; Disease Models, Animal; DNA microarrays; DNA Primers; Gene expression; Gene Knockdown Techniques; Genes; Humans; IL-1β; Immunohistochemistry; Inflammation; Inflammation Mediators - physiology; Inhibition (psychology); Kinases; Medicine; Memory; Mice; Mice, Transgenic; Microglia; Neurodegeneration; Neurodegenerative diseases; Neurological Disorders/Alzheimer Disease; Neurons; Neuroscience; Neuroscience/Neuronal and Glial Cell Biology; Neurosciences; Nitric-oxide synthase; Pathogenesis; Pathology/Neuropathology; Peptides; Pharmacology; Plaques; Protein binding; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; Rodents; Senile plaques; Signal transduction; Target marketing; Transcription factors; Transgenic animals; Transgenic mice; Tumor necrosis factor-α; β-Amyloid
• DOI: 10.1371/journal.pone.0008840
• ISSN: 1932-6203

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.