Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies

Higuchi, Makoto; Zhang, Bin; Forman, Mark S.; Yoshiyama, Yasumasa; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1523/jneurosci.2691-05.2005

Cited by 111 publications

(94 citation statements)

References 67 publications

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“…Most likely, this is a compensatory phenomenon, which, however, is not enough to reach or to exceed the level seen in the nondiseased group. Since dysfunctional oligodendrocytes have been shown to contribute to axonal degeneration and myelin loss, this could suggest that the myelin loss in the LCS is not just secondary to upper motor neuron damage [10,11,13,22]. This is also supported by studies on mice harboring mutations that cause oligodendroglial dysfunction and showing axonal degeneration, albeit in the presence of relatively preserved myelin sheaths [23,24].…”

Section: Discussionmentioning

confidence: 99%

Oligodendroglial Response in the Spinal Cord in TDP-43 Proteinopathy with Motor Neuron Involvement

Rohan¹,

Matěj

Rusina

et al. 2014

Neurodegener Dis

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Background: TDP-43 proteinopathies represent a spectrum of neurodegenerative disorders. Variable clinical presentations including frontotemporal dementia, amyotrophic lateral sclerosis (ALS) and mixed forms are associated with the spatial heterogeneity of the TDP-43 pathology. Recent studies have emphasized the role of oligodendrocytes in the pathogenesis of ALS. Objective: To evaluate whether TDP-43 proteinopathies are associated with an oligodendroglial response. Methods: We performed a study on 7 controls and 10 diseased patients with spinal cord involvement. Using the oligodendroglia-specific antibody TPPP/p25, we assessed oligodendrocyte density in the lateral corticospinal tracts (LCSs) along with the presence of perineuronal oligodendrocytes (PNOGs) in the anterior horns. We performed a densitometry of myelin basic protein (MBP) immunoreactivity. The numbers of TDP-43 and p62 immunoreactive inclusions were counted in both the LCSs and the anterior horns. Results: Double immunolabeling confirmed that oligodendrocytes harbor TDP-43 inclusions. In the LCSs, MBP density, but not the number of oligodendrocytes, was decreased in the diseased group. However, oligodendrocyte counts in the LCS correlated positively, and the density of MBP inversely, with the number of neuronal inclusions in the anterior horn, suggestive of a compensatory response of oligodendrocytes. The number of neurons with PNOGs correlated with the amount of inclusions. Conclusion: Our study further emphasizes the importance of oligodendroglia in the pathogenesis of TDP-43 proteinopathies with spinal cord involvement.

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Section: Discussionmentioning

confidence: 99%

Oligodendroglial Response in the Spinal Cord in TDP-43 Proteinopathy with Motor Neuron Involvement

Rohan¹,

Matěj

Rusina

et al. 2014

Neurodegener Dis

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“…This finding is similar to JNPL3 mice, 24 and various other models of tauopathy, which have been reported to have tau pathology in oligodendroglial cells. 25,26 mTau mice also develop vacuolization in the neuropil occurring primarily in the hippocampus with age ( Figure 6). The vacuolization tracks with transgene expression level and significantly increases with age, genotype, and tau burden (Figure 6, D-F), although the severity is variable between transgenic mice (Supplemental Figure S3, see http://ajp.amjpathol.org).…”

Section: Neurodegenerative Changes Accompany Pathology In Mtau Micementioning

confidence: 99%

Overexpression of Wild-Type Murine Tau Results in Progressive Tauopathy and Neurodegeneration

Adams

Crook

DeTure

et al. 2009

The American Journal of Pathology

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Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer's disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies. Abnormal accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles (NFTs), is the defining pathological feature of neurodegenerative diseases termed tauopathies. Six major tau protein isoforms are generated in adult human brain by alternative splicing of the tau (MAPT) gene, 1,2 and studies of mutations within this gene have provided insight into potential mechanisms for the pathological aggregation of tau proteins.3,4 With use of a single isoform of mutant human tau, transgenic mice have been generated (reviewed in 5 ) that recapitulate many features of human tauopathy; however, most tauopathies are not associated with specific MAPT mutations. Because normal and mutant tau proteins appear to have functional differences, 6 -8 the mechanism of tau pathology development, neuronal loss, and interactions with other proteins may also differ between sporadic tauopathies and cases linked to specific mutations. Previous attempts to create a wild-type tauopathy model through overexpression of a single wild-type human tau isoform have generally led to minimal pathological changes. Although these models have been useful in studying early aspects of tauopathy, they do not mimic normal gene regulation or tau isoform profiles in the brain. Development of a mouse model overexpressing the entire human tau transgene (8c mice) was expected to overcome this limitation. However, these mice failed to elicit notable tau pathology, but did result in a significant shift in exon 10...

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“…However, tau overexpression in oligodendrocytes has detrimental effects. Oligodendrocytes prepared from transgenic mice overexpressing human tau (wild type or the P301L mutation) under a CNP-promoter (Higuchi et al, 2005) were not viable for more than 5 days. MTs were extremely thin and defects in the MT network were observed (Richter-Landsberg, 2008).…”

Section: Microtubules and The Role Of Tau In Oligodendrocytesmentioning

confidence: 99%

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

Richter‐Landsberg¹

2016

Biological Chemistry

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Abstract:Oligodendrocytes are dependent on an intact, dynamic microtubule (MT) network, which participates in the elaboration and stabilization of myelin forming extensions, and is essential for cellular sorting processes. The microtubule-associated protein tau is constituent of oligodendrocytes. During culture maturation it is developmentally regulated and important for MT stability, MT formation and intracellular trafficking. Downregulation of tau impairs process outgrowth and the transport of myelin basic protein (MBP) mRNA to the cell periphery. Cells fail to differentiate into MBP-expressing, sheet-forming oligodendrocytes. Tau-positive inclusions originating in oligodendrocytes and white matter pathology are prominent in frontotemporal dementias, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. An impairment or overload of the proteolytic degradation systems, i.e. the ubiquitin proteasomal system and the lysosomal degradation pathway, has been connected to the formation of protein aggregates. Large protein aggregates are excluded from the proteasome and degraded by autophagy, which is a highly selective process and requires receptor proteins for ubiquitinated proteins, including histone deacetylase 6 (HDAC6). HDAC6 is present in oligodendrocytes, and α-tubulin and tau are substrates of HDAC6. In this review our current knowledge of the role of tau and protein aggregate formation in oligodendrocyte cell culture systems is summarized.

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Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies

Cited by 111 publications

References 67 publications

Oligodendroglial Response in the Spinal Cord in TDP-43 Proteinopathy with Motor Neuron Involvement

Oligodendroglial Response in the Spinal Cord in TDP-43 Proteinopathy with Motor Neuron Involvement

Overexpression of Wild-Type Murine Tau Results in Progressive Tauopathy and Neurodegeneration

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

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