Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease.
Huntington's Disease (HD) is characterized primarily by neuropathological changes in the striatum, including loss of medium-spiny neurons, nuclear inclusions of the huntingtin protein, gliosis, and abnormally high iron levels. Information about how these conditions interact, or about the temporal order in which they appear, is lacking. This study investigated if, and when, iron-related changes occur in the R6/2 transgenic mouse model of HD and compared the results with those from HD patients. Relative to wild-type mice, R6/2 mice had increased immunostaining for ferritin, an iron storage protein, in the striatum beginning at 2-4 weeks postnatal and in cortex and hippocampus starting at 5-7 weeks. The ferritin staining was found primarily in microglia, and became more pronounced as the mice matured. Ferritin-labeled microglia in R6/2 mice appeared dystrophic in that they had thick, twisted processes with cytoplasmic breaks; some of these cells also contained the mutant huntingtin protein. Brains from HD patients (Vonsattel grades 0-4) also had increased numbers of ferritin-containing microglia, some of which were dystrophic. The cells were positive for Perl's stain, indicating that they contained abnormally high levels of iron. These results provide the first evidence that perturbations to iron metabolism in HD are predominately associated with microglia and occur early enough to be important contributors to HD progression.
Simmons
Danielle A
DA
Department of Psychiatry and Human Behavior, University of California, Irvine, California 92697-4292, USA. simmonsd@uci.edu
Casale
Malcolm
M
Alcon
Betzi
B
Pham
Nha
N
Narayan
Natasha
N
Lynch
Gary
G
D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005293:Ferritins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006816:Huntington Disease / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D013194:Staining and Labeling / Q000379:methods
D005293:Ferritins; D007501:Iron