Progressive White Matter Pathology in the Spinal Cord of Transgenic Mice Expressing Mutant (P301L) Human Tau

J Neurocytol. 2005 Dec;34(6):397-410. doi: 10.1007/s11068-006-8726-0. Epub 2006 Aug 10.

Abstract

Transgenic mice expressing mutant (P301L) tau develop paresis, neurofibrillary tangles and neuronal loss in spinal motor neurons beginning at 4 to 6 months of age. Astrocytes and oligodendrocytes acquire filamentous tau inclusions at later ages. Here we report pathology in the spinal white matter of these animals. Progressive white matter pathology, detected as early as 2 months of age, was most marked in lateral and anterior columns, with sparing of posterior columns until late in the disease. Early changes in Luxol fast blue/periodic acid Schiff (LFB/PAS) and toluidine blue stained sections were vacuolation of myelin followed by accumulation of myelin figures within previous axonal tubes and finally influx of PAS-positive macrophages. Myelin debris and vacuoles were found in macrophages. At the ultrastructural level, myelinated axons showed extensive vacuolation of myelin sheaths formed by splitting of myelin lamellae at the intra-period line, while axons were atrophic and contained densely packed neurofilaments. Other axons were lost completely, resulting in collapse and phagocytosis of myelin sheaths. Also present were spheroids derived from swollen axons with thin myelin sheaths containing neurofilaments, tau filaments and degenerating organelles. Many oligodendrocytes had membrane-bound cytoplasmic bodies composed of tightly stacked lamellae capped by dense material. The vacuolar myelopathy in this model to some extent resembles that reported in acquired immune deficiency syndrome and vitamin B12 deficiency. The progressive axonal pathology is most consistent with a dying-back process caused by abnormal accumulation of tau in upstream neurons, while vacuolar myelinopathy may be a secondary manifestation of neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / pathology
  • Axons / ultrastructure
  • Disease Models, Animal
  • Disease Progression
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Macrophages / ultrastructure
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Mutation / genetics
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology
  • Myelin Sheath / ultrastructure
  • Myelitis / genetics
  • Myelitis / metabolism
  • Myelitis / pathology
  • Nerve Fibers, Myelinated / metabolism*
  • Nerve Fibers, Myelinated / pathology*
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology*
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Oligodendroglia / ultrastructure
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Spinal Cord Diseases / genetics
  • Spinal Cord Diseases / metabolism
  • Spinal Cord Diseases / pathology*
  • Vacuoles / metabolism
  • Vacuoles / pathology
  • Vacuoles / ultrastructure
  • Wallerian Degeneration / genetics
  • Wallerian Degeneration / metabolism
  • Wallerian Degeneration / pathology*
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • tau Proteins