Glial activation and TNFR-I upregulation precedes motor dysfunction in the spinal cord of mnd mice.
Mice homozygous for the spontaneous motor neuron degeneration mutation (mnd) show at the age of 8 months a marked impairment of the motor function and accumulation of lipofuscin granules in the cytoplasm of almost all neurons of the central nervous system. We previously reported a significant increase in GFAP protein levels in the lumbar spinal cord homogenates by western blot analysis and upregulation of TNF, a proinflammatory cytokine, in the motor neurons of lumbar spinal cord of mnd mice, already in a presymptomatic stage (4 months of age). In the present study, using immunohistochemical analysis, we performed a time course in mnd mice (1, 4 and 9 months of age) evaluating the expression and the distribution of astroglial and microglial cells and the expression of both TNF receptors, TNFR-I and TNFR-II. We observed a marked increase in astroglial and microglial cells and in TNFR-I immunoreactivity already at the 4th month. Since motor neuron dysfunction occurs in mnd mice in the absence of evident loss of spinal motor neurons, the present results indicate that the activation of microglial cells and astrocytes is independent from neuronal degeneration. The role of TNF and TNFR-I on motor neurons is still to be demonstrated.
Mennini
Tiziana
T
Department Molecular Biochemistry and Pharmacology, Mario Negri Institute for Pharmacological Research, Via Eritrea, 62, 20157, Milan, Italy. tiziana@marionegri.it
Bigini
Paolo
P
Cagnotto
Alfredo
A
Carvelli
Lucia
L
Di Nunno
Patrizia
P
Fumagalli
Elena
E
Tortarolo
Massimo
M
Buurman
Wim A
WA
Ghezzi
Pietro
P
Bendotti
Caterina
C
D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism*; D001253:Astrocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D039481:CD11b Antigen / Q000032:analysis; D015870:Gene Expression / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000737:chemistry / Q000166:cytology; D016472:Motor Neuron Disease / Q000209:etiology* / Q000503:physiopathology; D009046:Motor Neurons / Q000737:chemistry; D009457:Neuroglia / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D037121:Plant Lectins / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation / Q000235:genetics
D015703:Antigens, CD; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; C045475:Griffonia simplicifolia lectins; D037121:Plant Lectins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II