Progressive white matter pathology in the spinal cord of transgenic mice expressing mutant (P301L) human tau

Mayo Clinic College of Medicine, Jacksonville, Florida, 32224, USA.
Journal of Neurocytology (Impact Factor: 1.94). 12/2006; 34(6):397-410. DOI: 10.1007/s11068-006-8726-0
Source: PubMed

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.

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    • "The presence of extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) are 2 of the distinctive postmortem features of AD. In addition, there is mounting experimental support for a role of tau in white matter (WM) degeneration during the early etiology of AD (Amlien et al., 2013; Bartzokis et al., 2004; Hertze et al., 2013) and tauopathy mouse models (Lin et al., 2005; Zehr et al., 2004). Tau protein is enriched in healthy axons (Goedert, 2004), but a phosphorylated tau species that translocates to the cell soma, dendrites, synaptic terminals, and glial cells increases in AD (Janke et al., 1996) and is associated with destructive cell loss (Kowall and Kosik, 1987). "
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    ABSTRACT: Elevated expression of human hyperphosphorylated tau is associated with neuronal loss and white matter (WM) pathology in Alzheimer's disease (AD) and related neurodegenerative disorders. Using in vivo diffusion tensor magnetic resonance imaging (DT-MRI) at 11.1 Tesla we measured age-related alterations in WM diffusion anisotropy indices in a mouse model of human tauopathy (rTg4510) and nontransgenic (nonTg) control mice at the age of 2.5, 4.5, and 8 months. Similar to previous DT-MRI studies in AD subjects, 8-month-old rTg4510 mice showed lower fractional anisotropy (FA) values in WM structures than nonTg. The low WM FA in rTg4510 mice was observed in the genu and splenium of the corpus callosum, anterior commissure, fimbria, and internal capsule and was associated with a higher radial diffusivity than nonTg. Interestingly, rTg4510 mice showed lower estimates for the mode of anisotropy than controls at 2.5 months suggesting that changes in this diffusivity metric are detectable at an early stage preceding severe tauopathy. Immunogold electron microscopy partly supports our diffusion tensor imaging findings. At the age of 4 months, rTg4510 mice show axonal tau inclusions and unmyelinated processes. At later ages (12 months and 14 months) we observed inclusions in myelin sheath, axons, and unmyelinated processes, and a "disorganized" pattern of myelinated fiber arrangement with enlarged inter-axonal spaces in rTg4510 but not in nonTg mice. Our data support a role for the progression of tau pathology in reduced WM integrity measured by DT-MRI. Further in vivo DT-MRI studies in the rTg4510 mouse should help better discern the detailed mechanisms of reduced FA and anisotropy mode, and the specific role of tau during neurodegeneration.
    Neurobiology of aging 12/2013; 35(6). DOI:10.1016/j.neurobiolaging.2013.12.009 · 4.85 Impact Factor
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    • "Ultrastructural studies have been undertaken on other tau mutant mice such as the JNPL3 mutants (Lin et al. 2003b; Lin et al. 2005), but not on the rTg4510 mutant, in which tau expression is restricted to the forebrain. This is in contrast to JNPL3 mutants, in which the expression of tau pathology develops primarily in brainstem and spinal cord (Janus 2008; Lin et al. 2005). Despite the difference in expression pattern, JNPL3 tau pathology is similar to rTg4510 in many respects, including swollen axons, degenerating myelin, NFTs, and active microglial cells (Lin et al. 2003b; Lin et al. 2005). "
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    ABSTRACT: rTg4510 transgenic (TG) mice overexpress mutant (P301L) human tau protein. We have compared the dorsal premotor cortex of TG mice versus non-transgenic (NT) mice at 4, 9, and 13 months of age, using light (LM) and electron microscopy (EM). LM assessment shows that cortical thickness in TG mice is reduced by almost 50% from 4 to 13 months of age, while at the same time layer I thickness is reduced by 80%, with most of the cortical thinning occurring between 4 and 9 months. In TG mice, spherical, empty vacuoles, up to 60 μm in diameter, become increasingly abundant with age and by 9 months, pyramidal and non-pyramidal neurons with large intracellular tangles of tau protein are common throughout the cortex. These tangles occur in the perikarya; we have not observed them entering into cellular processes, nor have we observed ghost tangles in the intercellular matrix. In TG mice, nerve fiber pathology is widespread by 13 months, and split myelin sheaths, ballooned sheaths, and swollen axons containing mitochondrial aggregations are all common. Astrocytes become increasingly filled with glial filaments as TG mice age, and microglial cells almost always contain phagocytic inclusions. However, no glial cells are seen to contain tau in their cytoplasm. These observations add to the base of knowledge available on this commonly employed model of tauopathy.
    Brain Structure and Function 03/2011; 216(1):31-42. DOI:10.1007/s00429-010-0295-4 · 4.57 Impact Factor
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    • "Paraffin-embedded sections were also stained for the toluidine blue staining and hematoxylin and eosin. Luxol fast blue/periodic acid Schiff (LFB/PAS) staining was performed as previously described (Lin et al., 2005). "
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    ABSTRACT: Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2010; 30(32):10851-9. DOI:10.1523/JNEUROSCI.1630-10.2010 · 6.75 Impact Factor
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