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 multifunctional proteins: clusterin and two complement cascade components, C1q and C4. Previous work from this and other laboratories has established that clusterin, Clq and C4 messenger RNAs are elevated during Alzheimer's disease, and in response to deafferenting and excitotoxic brain lesion. This study addresses hippocampal clusterin, ClqB and C4 expression in response to neurotoxins that caused selective neuron death. Kainate, which preferentially kills hippocampal CA3 pyramidal neurons but not dentate gyrus granule neurons induced clusterin immunoreactivity in CA1 and CA3 pyramidal neurons and adjacent astrocytes, but not in dentate gyrus granule neurons. In contrast, colchicine, which preferentially kills the dentate gyrus granule neurons, induced clusterin immunoreactivity in the local neuropil as punctate deposits, but not in the surviving or degenerating dentate gyrus granule neurons. Clusterin messenger RNA was increased in astrocytes. ClqB and C4 messenger RNAs increased within 48 h after kainate injections, particularly in the CA3 pyramidal layer, less in the dentate gyrus-CA4, and less in CA1. Clq immunoreactivity was detected in CA1 pyramidal neurons and also as small punctate deposits in the CA1 region at eight and 14 days after kainate. The increase of both clusterin and ClqB messenger RNAs after kainate injections was blocked by barbiturates that prevented seizures and neurodegeneration. In primary hippocampal neuronal cultures treated with glutamate, a subpopulation of cultured neurons that survived glutamate toxicity also had parallel elevations of clusterin and ClqB messenger RNA. In conclusion, cytotoxins that target selective hippocampal neurons increase the expression of both clusterin and ClqB in vivo and in vitro. These results show that elevations of clusterin messenger RNA or protein can be dissociated from each other and from cell death. These increased messenger RNAs were associated with immunoreactive deposits that differed by cell type and intra- versus extracellular locations. These results suggest that the complement system is involved in brain responses to injury.
Rozovsky
I
I
Neurogerontology Division, Andrus Gerontology Center, Los Angeles, CA.
Morgan
T E
TE
Willoughby
D A
DA
Dugichi-Djordjevich
M M
MM
Pasinetti
G M
GM
Johnson
S A
SA
Finch
C E
CE
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death; D051152:Clusterin; D015922:Complement C1q / Q000096:biosynthesis* / Q000235:genetics; D003181:Complement C4 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology / Q000633:toxicity*; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D051152:Clusterin; D003181:Complement C4; D006023:Glycoproteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018698:Glutamic Acid; D015922:Complement C1q; D007608:Kainic Acid