Mice with targeted disruption of neurofilament light subunit display formation of protein aggregation in motoneurons and downregulation of complement receptor type 3 α subunit in microglia in the spinal cord at their earlier age: A possible feature in pre-clinical development of neurodegenerative diseases

Abstract

The pathogenesis of neurodegenerative diseases prior to the onset of symptoms is generally not clear. The present study has employed a mouse model with a lack of the low-molecular-weight neurofilament subunit (NFL-/-), in which formation of protein aggregates occurs in neurons, to investigate glial cellular reactions in the lumbar cord segments of NFL-/- mice at ages from 1 to 6 months. Age-matched C57BL/6 mice serve as the control. Apparent neurofilament positive aggregates in the cytoplasm of motoneurons have been observed in NFL-/- mice. However, there were no noticeable changes in microglial numbers and GFAP staining of astrocytes. Unexpectedly, a downregulation in expression of complement receptor type 3 α subunit (CD11b) was detected in the spinal cord of NFL-/- mice, while there was no obvious difference between NFL-/- and C57BL/6 mice in the CD11b staining intensity of macrophages from livers and spleens. In addition, retardation in morphological transformation from activated to amoeboid microglia in response to sciatic nerve injury, differential expressions of some cytokines in the lumbar cord segments and induction of Iba-1 (ionized calcium-binding adaptor molecule-1) expression in microglia were observed in NFL-/- mice. Our results suggest not only the existence of an inhibitory niche for CD11b expression in microglia in the lumbar cord segments of NFL-/- mice but also differential microglial reactions between earlier and later stages of neuropathogenesis. Although the real cause for such inhibition is still unknown, this effect might play a particular role in the survival of the abnormal protein aggregate-bearing motoneurons in the early development stage of neurodegeneration in the NFL-/- mice. © 2006 Elsevier B.V. All rights reserved.