This project will examine the expression of a key group of regulatory proteins, the suppressor of cytokine signaling (SOCS), a family of 8 intracellular proteins consisting of SOCS 1-7 and cytokine-inducible Src homology 2 domain containing protein (CIS) in human Alzheimer's disease (AD) brains and human neural cells. The SOCS proteins regulate signal transduction of the STAT pathway by direct inhibitory interactions with cytokine receptors and signaling proteins, and to target these complexes for proteosomal degradation. SOCS are immediate early proteins with short half-lives;their presence in tissue indicates ongoing responses to pathology. As evidence is emerging for the involvement of SOCS proteins in diseases of the human immune system, this raises the possibility that therapeutic strategies based on the manipulation of SOCS activity, for example earlier in AD, might be of clinical benefit. The central hypothesis is that induction of certain SOCS gene products will be neuroprotective due to their effects on reducing direct and indirect consequences of inflammation. We will examine in vivo whether there is a deficit or overproduction of each SOCS in relation to AD pathology, and which cell types are expressing these proteins. This will be examined in two specific aims employing human brain tissue samples, and human brain-derived cells.
Specific Aim 1 : To correlate expression and localization of SOCS 1-7 mRNA and protein in AD affected brains in relation to markers of activated JAK/STAT, inflammation and AD pathology. The goal of this aim is to define how SOCS expression correlates with disease state, and at the cellular level whether it correlates with activated markers of the JAK/STAT pathway and other markers of inflammation and neurodegeneration.
This aim will not only determine which of the SOCS are expressed and up-or downregulated in AD, but how they interact with pathological structures.
This aim will study expression of all SOCS proteins, but focus on SOCS-3 due to preliminary results showing strong localization to neurons.
Specific Aim 2 : To identify and test agents that induce expression of SOCS in microglia, astrocytes, vascular endothelial cells and neurons that result in reduced Ab induced inflammatory activation or neurotoxicity. The goal of this aim is to firstly determine the cell type specificity of SOCS expression, secondly identify therapeutic agents that can induce expression of SOCS (particularly SOCS-3) in the absence of inflammatory cytokines. This property has been shown for simvastatin, the agent widely used to treat hypercholesterolemia. Human microglia, astrocytes, vascular endothelial cells and neurons will be used to explore the effects of a range of therapeutic agents on SOCS expression. Secondly, we will determine whether pretreatment with these agents reduce Ab induced inflammatory indices.
The relevance of this research is that it will investigate an area of anti-inflammatory research that has never been studied in the Alzheimer's disease brain, and where there are very limited studies in human brain at all. This class of proteins (suppressor of cytokine signaling) is a potentially powerful new target for anti-inflammatory therapy. This project will answer two key questions;how are the suppressor of cytokine signaling proteins involved with AD pathology, and is there a deficiency of these proteins in disease brains, and secondly, can one use drugs to increase their levels of expression in brain so that they are functional.
