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P4‐030: Genetically Modified ACE10‐Macrophages Exhibit Superior Capacity to Eradicate Structurally Defined AB Forms Linked to Alzheimer’s Disease
Author(s) -
Rentsendorj Altan,
Koronyo Yosef,
Hayden Eric Y.,
Sheyn Julia,
Fuchs Dieu-Trang S.,
Li Songlin,
Black Keith L.,
Bernstein Kenneth E.,
Teplow David B.,
Fuchs Sebastien,
Maya Koronyo-Hamaoui
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.2119
Subject(s) - genetically modified mouse , immune system , transgene , phagocytosis , microglia , phenotype , in vivo , chemistry , microbiology and biotechnology , biology , immunology , inflammation , biochemistry , genetics , gene
Background: TgAD mouse models of Alzheimer’s disease treated with scyllo-inositol showed reduced amyloid load and reversed behavioural changes (McLaurin et al 2006 Nat Med). scyllo-Inositol is a competitive inhibitor of myo-inositol for transport across the blood brain barrier leading to reduction in intracellular and brain myo-inositol levels (Fenili et al 2011 PLOSONE). Clinical trial results indicate scyllo-inositol treatment reduced agitation and aggression in patients with Alzheimer’s disease. The mechanism of action has yet to be proven, although reduction of brain myoinositol concentration is a candidate. Methods: Gene expression for TgAD and nonTg littermate mice treated with scyllo-inositol were compared to untreated control mice (n1⁄43) using Affymetrix mouse genome 430 microarrays. The data (FDR1⁄40.05 FC>2) was analyzed using The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Qiagen’s Ingenuity Pathway Analysis. Results:Three comparisons were analyzed, nontransgenic (nTg) hippocampus, nTg cortex, and transgenic (Tg) hippocampus. nTg hippocampal gene expression identified 596 probe sets that met the predetermined cut-offs, nTg cortical gene expression identified 725, and Tg hippocampal gene expression identified 541 probe sets. nTg cortex differentially expressed only 18 probe sets between treated and untreated mice, thus analysis was not performed. Synaptic transmission was a common enriched function from DAVID for all three comparisons. From Ingenuity Pathway Analysis, the common top canonical pathway affected by scyllo-inositol treatment in hippocampus and cortex of nTg is glutamate receptor signalling, which is not affected in Tg hippocampus. Common top upstream regulators between all three comparisons were BDNF and HTT. Conclusions: scyllo-Inositol treatment modulates gene expression differentially in TgAD versus nTgmice suggesting that treatment has Ab-dependent and independent effects. Ingenuity Pathways Analysis identified gene expression changes in TgAD mice that have been previously linked to Alzheimer’s disease patients, thus supporting the pathways identified in this analysis.