Large numbers of activated glia (microglia and astrocytes) are a common pathological feature of many neurodegenerative disorders, including Alzheimer's disease (AD) where activated glia are found surrounding amyloid plaques. Apolipoprotein E (apoE) is also found associated with these plaques and is synthesized and secreted primarily by glial cells. In vitro, we have demonstrated amyloid-beta (Abeta) induces glial activation as well as an increase in endogenous apoE that acts to limit the inflammatory response. We have also demonstrated that apoE receptors mediate both Abeta-induced glial activation and the increase in apoE. Thus, our hypothesis is that apoE is an endogenous antiinflammatory protein produced by activated glia as a unique response to Abeta via a mechanism mediated by apoE receptors. This Abeta-induced increase in apoE serves as a negative feedback response to limit further glial activation. Disruption of this process may contribute to unregulated neuroinflammation leading to neurodegenerative events. The overall goal of this grant is to define the pathway whereby Abeta interacts with apoE receptors to induce glia activation and increase apoE. In addition, we will determine the effect of this glial-mediated process on neuronal viability in vitro and in vivo.
The specific aims for this proposal include: 1. Determine the effect of oligomeric and fibrillar Abeta1-42 on glial activation, apoE levels and neuronal viability. Hypothesis: Oligomeric Abeta1-42 is a more potent inducer of glial activation than fibrillar Abeta1-42. 2. Determine the mechanism for Abeta-induced glial activation. Hypothesis: Lipoprotein receptor-related protein (LRP) mediates Abeta-induced glial activation. 3. Determine the mechanism for the Abeta-induced increase in apoE. Hypothesis: Low-density lipoprotein receptor (LDLR) mediates Abeta-induced increases in apoE. 4. Define the pattern and isoform-specificity of apoE's anti-inflammatory activity. Hypothesis: ApoE4 is a less efficient anti-inflammatory agent than apoE2 or E3. This grant is designed to determine how Abeta, apoE receptors, and apoE interact to regulate glial activation. Inhibition of the glial-mediated inflammatory response may be one way that apoE and apoE receptors preserve neuronal viability. In addition, if apoE4 is a less efficient anti-inflammatory agent than apoE2 or E3, this activity would account for the correlation between epsilon4 and AD. Understanding the apoE receptor-mediated mechanisms whereby Abeta induces glial cell activation and apoE antagonizes the process may provide additional sites for intervening in neuroinflammatory and neurodegenerative processes.
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