SELECTIVE EXPRESSION OF CLUSTERIN (SGP-2) AND COMPLEMENT C1QB AND C4 DURING RESPONSES TO NEUROTOXINS IN-VIVO AND IN-VITRO

This study concerns expression of the genes encoding three multifuncti onal proteins: cluslerin and two complement cascade components, C1q an d C4. Previous work from this and other laboratories has established t hat clusterin, C1q and C4 messenger RNAs are elevated during Alzheimer 's disease, and in response to deafferenting and excitotoxic brain les ions. This study addresses hippocampal clusterin, C1qB and C4 expressi on in response to neurotoxins that caused selective neuron death. Kain ate, which preferentially kills hippocampal CA3 pyramidal neurons but not dentate gyrus granule neurons induced clusterin immunoreactivity i n CA1 and CA3 pyramidal neurons and adjacent astrocytes, but not in de ntate gyrus granule neurons. In contrast, colchicine, which preferenti ally kills the dentate gyrus granule neurons, induced clusterin immuno reactivity in the local neuropil as punctate deposits, but not in the surviving or degenerating dentate gyrus granule neurons. Clusterin mes senger RNA was increased in astrocytes. C1qB and C4 messenger RNAs inc reased within 48 h after kainate injections, particularly in the CA3 p yramidal layer, less in the dentate gyrus-CA4, and less in CA1. C1q im munoreactivity was detected in CA1 pyramidal neurons and also as small punctate deposits in the CA1 region at eight and 14 days after kainat e. The increase of both clusterin and ClqB messenger RNAs after kainat e injections was blocked by barbiturates that prevented seizures and n eurodegeneration. In primary hippocampal neuronal cultures treated wit h glutamate, a subpopulation of cultured neurons that survived glutama te toxicity also had parallel elevations of clusterin and C1qB messeng er RNA. In conclusion, cytotoxins that target selective hippocampal ne urons increase the expression of both clusterin and C1qB in vivo and i n vitro. These results show that elevations of clusterin messenger RNA or protein can be dissociated from each other and from cell death. Th ese increased messenger RNAs were associated with immunoreactive depos its that differed by cell type and intra- versus extracellular locatio ns. These results suggest that the complement system is involved in br ain responses to injury.