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Genetics ignite focus on microglial inflammation in Alzheimer's disease.

ABSTRACT: In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD.

SUBMITTER: Malik M

PROVIDER: S-EPMC4595327 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Genetics ignite focus on microglial inflammation in Alzheimer's disease.

Malik Manasi M Parikh Ishita I Vasquez Jared B JB Smith Conor C Tai Leon L Bu Guojun G LaDu Mary Jo MJ Fardo David W DW Rebeck G William GW Estus Steven S

Molecular neurodegeneration 20151005

In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological f ...[more]

PMID: 26438529

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Project description:Background: Alzheimer's disease (AD) is characterized by amyloid beta (A?) accumulation in the brain, which triggers the activation of microglia; in turn, microglia release neuroinflammatory factors capable of damaging neurons. Thus, a therapeutic approach targeting this sustained microglia-induced inflammatory response deserves investigation. Here, we examined whether oxiracetam (ORC), a nootropic of the racetam family, can indirectly prevent A?-induced neurotoxicity by attenuating microglial activation. Methods: A?42 oligomers were used to stimulate BV2 microglial cells, and the morphological changes and phagocytic capacity of BV2 cells were evaluated using fluorescence microscopy. We used quantitative reverse transcription polymerase chain reaction to assess the inhibitory effects of ORC on A?-induced mRNA levels of interleukin-1? (IL-1?), IL-6, and tumor necrosis factor-? (TNF-?); enzyme-linked immunosorbent assay was used to examine the productions of these cytokines. We also assessed the mRNA level of inducible nitric oxide synthase and the production of nitric oxide (NO). The conditioned medium from BV2 cells was used to culture hippocampal HT22 cells to assess indirect toxicity using the MTT assay. Results: ORC prevented the A?-induced activation of BV2 cells, as reflected by reduced morphological changes and phagocytic ability. In addition, ORC downregulated the expression of A?-induced cytokines (IL-1?, IL-6, and TNF-?) and the production of NO in BV2 cells. Furthermore, ORC protected HT22 cells from indirect damage evoked by A?-treated BV2 cell-conditioned medium, but not from direct A?-induced toxicity. Conclusions: ORC suppressed the activation of BV2 cells, decreased the production of A?-induced inflammatory molecules and NO in BV2 cells, and protected HT22 cells against indirect toxicity mediated by A?-treated BV2 cell-conditioned medium. Thus, ORC may exert a protective role in AD through attenuating the damage caused by inflammation and oxidative stress.

Dataset Information

Genetics ignite focus on microglial inflammation in Alzheimer's disease.

Publications

Genetics ignite focus on microglial inflammation in Alzheimer's disease.

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