Activation of calpain‐1 in myelin and microglia in the white matter of the aged rhesus monkey

Ultrastructural disruption of myelin sheaths and a loss of myelin with age are well‐documented phenomena in both the human and rhesus monkey. Age‐dependent activation of calpain‐1 (EC 3.4.22.52) has been suggested as a plausible mechanism for increased proteolysis in the white matter of the rhesus m...

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Published in:	Journal of neurochemistry Vol. 89; no. 2; pp. 430 - 441
Main Authors:	Hinman, Jason D., Duce, James A., Siman, Robert A., Hollander, William, Abraham, Carmela R.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Science Ltd 01-04-2004 Blackwell
Subjects:	aging Aging - metabolism Animals Biological and medical sciences Brain - cytology Brain - enzymology Calpain - metabolism Enzyme Activation - physiology Female Fundamental and applied biological sciences. Psychology Immunoblotting Isolated neuron and nerve. Neuroglia Macaca mulatta - metabolism Male microglia Microglia - enzymology myelin Myelin Sheath - enzymology oligodendrocyte proteolysis spectrin Spectrin - metabolism Vertebrates: nervous system and sense organs Spectrin Senescence Enzyme Myelin Cysteine endopeptidases Neuroglia Central nervous system Monkey Calpain White matter Encephalon Microglia Peptidases Vertebrata Mammalia Oligodendrocyte Proteolysis Primates Hydrolases Myelin sheath aging Age
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Summary:	Ultrastructural disruption of myelin sheaths and a loss of myelin with age are well‐documented phenomena in both the human and rhesus monkey. Age‐dependent activation of calpain‐1 (EC 3.4.22.52) has been suggested as a plausible mechanism for increased proteolysis in the white matter of the rhesus monkey. The present study documents activation of calpain‐1 throughout brain white matter in aged animals, evidenced by immunodetection of the activated enzyme as well as a calpain‐derived spectrin fragment in both tissue section and Triton X‐100‐soluble homogenate of subcortical white matter from the frontal, temporal, and parietal lobes. Separation of myelin fractions from brain stem tissue into intact and floating myelin confirmed previous reports of an age‐related increase in activated calpain‐1 in the floating fraction. Measurements of calpain‐1 activity using a fluorescent substrate revealed an age‐related increase in calpain‐1 proteolytic activity in the floating myelin fraction consistent with immunodetection of the activated enzyme in this fraction. Double‐immunofluorescence demonstrated co‐localization of activated calpain‐1 with human leukocyte antigen‐DR (HLA‐DR), a marker for activated microglia, suggesting that these cells represent the major source of the increase in activated calpain‐1 in the aging brain. These data solidify the role of calpain‐1 in myelin protein metabolism and further implicate activated microglia in the pathology of the aging brain.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3042 1471-4159
DOI:	10.1046/j.1471-4159.2004.02348.x