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including Salvia miltiorrhiza, Panax notoginseng and Dryobalanops. Aromatica Gaertner and is widely used to treat cardiovascular diseases. We investigated ...
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Sunday, July 14, 2013: Poster Presentations: P1

inflammatory activation of microglia. TLR mediated microglial activation can be beneficial by stimulating phagocytosis but can also be deleterious by endorsing Ab-stimulated release of neurotoxic molecules. TLRs transduce their signals through MyD88 and the serine/threonine IL-1 receptorassociated kinase (IRAK). The IRAK family of kinases generally upregulate TLR signaling, with the notable exception of the inhibitory kinase IRAK-M. IRAK-M expression is specific to cells of monocytic lineage, including microglia, and plays a critical role in the maintenance of innate immune homeostasis by dampening inflammation. Methods: We crossed mice deficient in IRAK-M (IRAK-M -/-) with mice over expressing mutant human amyloid precursor protein, the PSAPP mouse model of cerebral amyloidosis. Innate immune cell activation and cerebral A b burden were subsequently evaluated in age- and sex-matched littermates from PSAPPIRAK-M + and PSAPP- IRAK-M -/- mice at 15 and 25 months. Results: Immunohistochemistry for the reactive microglial marker Iba1 disclosed statistically significant increased expression in PSAPP- IRAK-M -/- vs. PSAPP- IRAK-M + mice in the hippocampus, cerebral cortex and entorhinal cortex (up 38-42%), brain regions associated with AD-type pathology in humans. Further, brain parenchymal Ab abundance was correspondingly attenuated in PSAPP- IRAK-M -/- mice as measured by ThioS staining and ELISA. Finally, in vivo quantification of Ab within Lamp2 + phagolysosomes revealed a microglial phagocytic mechanism of Ab clearance in IRAK-M knockouts. Conclusions: These data suggest that IRAK-M negatively regulates brain innate immunity in a mouse model of cerebral amyloidosis. Collectively then, disinhibition of IRAK-M represents a means to target migroglial remodeling and clearance of amyloid pathology.

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INTRACRANIAL ADMINISTRATION OF GAMMAGARD IVIG LOWERS AMYLOID AND MODULATES NEUROINFLAMMATORY PROFILES ALONG A DIFFERENT TIME-COURSE THAN ANTI-BETA-AMYLOID IGG: IMPLICATIONS FOR MECHANISM OF ACTION

Donna Wilcock, Tiffany Sudduth, Abigail Greenstein, University of Kentucky, Lexington, Kentucky, United States. Contact e-mail: donna. [email protected] Background: Gammargard IVIg is a therapeutic approach to treat Alzheimer’s disease currently in phase 3 clinical trials. Despite the reported efficacy of the approach, the mechanism of action is poorly understood. We have previously shown that intracranial injection of anti-Abantibodies into the frontal cortex and hippocampus reveals important information regarding the time-course of events once the agent is in the brain. In the current study we compared Gammagard IVIg, mouse pooled IgG and the anti-A b antibody 6E10. Methods: We injected Gammagard IVIg, mouse pooled IgG and the anti-A b antibody 6E10 intracranially into the frontal cortex and hippocampus of 9 month old APP/PS1 mice. We established a time-course of events ranging from 24 hours to 21 days post-injection. Results: Gammagard IVIg and pooled mouse IgG both significantly reduced amyloid deposition to the same degree as the 6E10 anti-Abantibody, however, the clearance was much slower to occur, happening between the 3 day and 7 day time-points. In contrast, as we have previously shown, amyloid reductions were apparent with the 6E10 anti-Abgroup at the 1-day time-point. Also, neuroinflammatory profiles were significantly altered by the antibody treatments. APP/PS1 transgenic mice at nine months of age typically exhibit an M2a inflammatory phenotype. Anti-AbIgG stimulated a brief M2b state, peaking at 2 days and resolving completely by 7 days. In contrast, Gammagard IVIg and pooled mouse IgG both stimulated an M2b response that peaked at 7 days and was sustained through the 14 day time-point, only resolving by 21 days. Conclusions: Because the neuroinflammatory switch occurs prior to the detectable reductions in amyloid deposition, we hypothesize that the Gammagard IVIg and pooled mouse IgG act as immune modulators and this immune modulation is responsible for the reductions in amyloid pathology. Future studies will focus on this mechanism of action to determine whether immune modulation avoids the cerebrovascular adverse events that have plagued the anti-Ab immunotherapy approaches.

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PREVENTIVE EFFECTS OF CARDIOTONIC PILLS ON WHITE MATTER DAMAGE AND NEUROINFLAMMATION INDUCED BY CHRONIC CEREBRAL HYPOPERFUSION IN A RAT MODEL

WonKyung Jeon1, Jihye Bang2, Ki-Mo Lee3, 1Korea Institute of Oriental Medicine, Daejeon, South Korea; 2Korea Institute of Oriental Medicine, Daejeon, South Korea; 3Herbal Medicine Research Division, Daejeon, South Korea. Contact e-mail: [email protected] Background: Cardiotonic pills (CP) is a commercial herbal medicine including Salvia miltiorrhiza, Panax notoginseng and Dryobalanops Aromatica Gaertner and is widely used to treat cardiovascular diseases. We investigated the effects of CP in rats with chronic cerebral hypoperfusion. Methods: Chronic cerebral hypoperfusion was induced in male Wister rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily administration of CP (200 mg/kg) was started on day 20 after BCCAo and continued for 42 days. Immunohistochemical analysis was performed in basal forebrain and white matter of BCCAo-induced rats by using myelin basic protein (MBP), Iba-1, OX-6 and choline acetyltransferase (ChAT) antibody. The expression level of mitogen-activated protein kinases (MAPKs), interleukin-1 b (IL-1 b), interleukin-6 (IL-6), cyclooxygenase2 (Cox-2), ChAT and MBP in the BCCAo brains was analyzed by Western blot. Results: In the white matter regions, treatment with CP improved the MBP levels decreased by chronic cerebral hypoperfusion and the levels of microglial activation mitigated (vehicle-treated BCCAo; 11.5 62.8 and CP-treated BCCAo; 9.062.3, P