Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy

Hampton, David W.; Webber, Daniel J.; Bilican, Bilada; Goedert, Michel; Spillantini, Maria Grazia; Chandran, Siddharthan

doi:10.1523/jneurosci.0834-10.2010

Cited by 109 publications

(120 citation statements)

References 56 publications

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“…1A). Despite the early development of tau pathology in P301S‐htau mice, significant neuronal loss has been detected only from 3 months of age (Hampton et al, 2010; Yang et al, 2015). Interestingly, in 2‐month‐old P301S‐htau mice toluidine blue staining of the ventral funiculus (embedded in resin) revealed a marked change in axonal calibre distribution and occasional myelin figures (concentrically layered myelin without axon) suggestive of Wallerian degeneration (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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Section: Resultsmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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“…The number of NeuN + dots per square was counted using the cellcounter program (ImageJ software; National Institutes of Health) with a fixed threshold. The cortical layers were defined as follows: layers II and III, 150 μm from the surface to a depth of 350 μm; layer IV, 350-550 μm from the surface; layer V, 550-750 μm from the surface (46). To count Purkinje cells, at least three sagittal sections (6 μm thick) per brain were cut and stained with calbindin antibody.…”

Section: Methodsmentioning

confidence: 99%

Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder

Malta

Fryer

Settembre

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

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The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1 −/− astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.ultiple sulfatase deficiency (MSD) is a lysosomal storage disorder (LSD) caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene that results in aberrant posttranslation modification of sulfatases (1). Sulfatases are a family of enzymes required for the turnover and degradation of sulfated compounds. Eight known metabolic disorders are caused by the deficiency of individual sulfatase activities. Six are LSDs (five mucopolysaccharidoses and metachromatic leukodystrophy); the remaining two disorders are caused by deficiency of nonlysosomal sulfatases. The impaired activity of all sulfatases in MSD is responsible for a very severe phenotype that combines all the clinical symptoms found in each individual sulfatase deficiency (2). As in many other LSDs, progressive and severe neurodegeneration is a prominent feature and is the most difficult challenge for therapy (3). Previous studies identified impaired autophagy in neurons as a crucial component in the pathogenic mechanisms leading to neurodegeneration in MSD as well as in other LSDs (4,5). This lysosomal accumulation of undegraded substrates results in defective degradation of autophagosomes and causes a block of the autophagy pathway leading to an accumulation of ubiquitinated proteins, dysfunctional mitochondria, and neurodegeneration. To date, research has focused on neurons, but the contribution of nonneuronal cells to the neuropathology of MSD has remained largely unexplored.Astrocytes play crucial roles in adult CNS homeostasis (6), including synaptic glutamate uptake (7), maintenance of extracellular potassium (8), and nutrient support for neuro...

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“…19 In addition, recent experimental studies with in vitro and mouse models of AD have linked both astrocytes and microglia to neurodegeneration 20 -25 and have shown that activated microglia can lead to hyperphosphorylation and aggregation. 26,27 The idea of reactive glia as a hostile environment for neurons in the context of neurodegeneration has been recently proposed by elegant studies 28,29 on amyotrophic lateral sclerosis and tauopathy mouse models. If this idea proves to apply to AD, an increasing number of reactive glial cells around dense-core plaques might well contribute to their local toxicity by releasing soluble biologically active toxic molecules, such as pro-inflammatory cytokines and reactive oxygen species.…”

Section: Implications For the Role Of Reactive Glial Cells In Admentioning

confidence: 99%

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

Serrano-Pozo

Mielke

Gómez-Isla

et al. 2011

The American Journal of Pathology

409

331

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Senile plaques are a prominent pathological feature of Alzheimer's disease (AD), but little is understood about the association of glial cells with plaques or about the dynamics of glial responses through the disease course. We investigated the progression of reactive glial cells and their relationship with AD pathological hallmarks to test whether glial cells are linked only to amyloid deposits or also to tangle deposition, thus integrating both lesions as a marker of disease severity. We conducted a quantitative stereology-based post-mortem study on the temporal neocortex of 15 control subjects without dementia and 91 patients with AD, including measures of amyloid load, neurofibrillary tangles, reactive astrocytes, and activated microglia. We also addressed the progression of glial responses in the vicinity (<50 m) of dense-core plaques and tangles. Although the amyloid load reached a plateau early after symptom onset, astrocytosis and microgliosis increased linearly throughout the disease course. Moreover, glial responses correlated positively with tangle burden, whereas astrocytosis correlated negatively with cortical thickness. However, neither correlated with amyloid load. Glial responses increased linearly around existing plaques and in the vicinity of tangles. These results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques. They also suggest that reactive glia might contribute to the ongoing neurodegeneration.

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Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy

Cited by 109 publications

References 56 publications

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

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