Microglial Activation Pathways - Regulation by Apoe

Laskowitz, Daniel

Abstract

Microglial activation is associated with most types of neuropathology, and recent evidence suggests that microglial activation may contribute to death of certain neurons. Microglial activation leads to death of selective populations of neurons in mixed neuronal/glial cultures. The microglial pathways involved in producing cytotoxins, particularly ones selective for neurons, remain poorly characterized. Zymosan, a classical phagocytosed macrophage activator, is a more neurotoxic microglial activator than lipopolysaccharide (LPS), a soluble endotoxin commonly used to activate microglia. Protein kinase C activation appears to account for the increased neurotoxicity of zymosan relative to LPS. Apolipoprotein E (apoE), a glial derived factor whose production increases dramatically after brain injury, has recently been shown to suppress microglial activation. One human apoE allele, apoE4, increases the risk of developing Alzheimers Disease relative to the more common alleles apoE2 and apoE3. Increasing evidence implicates apoE4 as increasing severity and worsening prognosis for other neuropathologies as well. ApoE4 is reportedly less effective than apoE2 or 3 at suppressing at least some forms of microglial activation. We propose to use cell cultures from transgenic mice expressing no apoE, murine apoE, human apoE2, 3 or 4 to investigate at which steps apoE inhibits microglial activation and whether there is a differential effect of the human apoE isoforms. In particular, we will determine whether apoE isoforms preferentially inhibit responses to soluble or phagocytosed stimuli, and whether neuron-specific toxin production is selectively inhibited by any of the endogenously produced apoE isoforms.