Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

Spittaels, Kurt; Haute, Chris Van den; Dorpe, Jo Van; Bruynseels, Koen; Vandezande, Kris; Laenen, Isabelle; Geerts, Hugo; Mercken, Marc; Sciot, Raf; Lommel, Alfons Van; Loos, Ruth J.F.; Leuven, Fred Van

doi:10.1016/s0002-9440(10)65533-2

Cited by 361 publications

(328 citation statements)

References 69 publications

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“…46 Overexpression of protein Tau inhibits kinesindependent trafficking of vesicles, mitochondria, and endoplasmic reticulum in neuro-2a cells, 47 and causes prominent axonopathy in htau-40 transgenic mice. 48 These data strengthen the importance of proper control by posttranslational modification of the microtule-associated protein Tau, its localization, and intracellular concentration, in vivo. We have shown that expression of ApoE4 in neurons results in hyperphosphorylation of protein Tau in brain 37 and in spinal cord (this study).…”

Section: Discussionmentioning

confidence: 56%

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

Tesseur

Dorpe

Bruynseels

et al. 2000

The American Journal of Pathology

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131

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The epsilon 4 allele of the human apolipoprotein E gene (ApoE4) constitutes an important genetic risk factor for Alzheimer's disease. Recent experimental evidence suggests that human ApoE is expressed in neurons, in addition to being synthesized in glial cells. Moreover, brain regions in which neurons express ApoE seem to be most vulnerable to neurofibrillary pathology. The hypothesis that the expression pattern of human ApoE might be important for the pathogenesis of Alzheimer's disease was tested by generating transgenic mice that express human ApoE4 in neurons or in astrocytes of the central nervous system. Transgenic mice expressing human ApoE4 in neurons developed axonal degeneration and gliosis in brain and in spinal cord, resulting in reduced sensorimotor capacities. In these mice, axonal dilatations with accumulation of synaptophysin, neurofilaments, mitochondria, and vesicles were documented, suggesting impairment of axonal transport. In contrast, transgenic mice expressing human ApoE4 in astrocytes remained normal throughout life. These results suggest that expression of human ApoE in neurons of the central nervous system could contribute to impaired axonal transport and axonal degeneration. The epsilon 4 allele of the apolipoprotein E (ApoE) gene is associated with Alzheimer's disease (AD), affecting the onset of the disease in an allele dose-dependent manner. 1,2 ApoE4 is associated with increased plaque load in AD 3-5 and early onset of neurofibrillary changes. 6 ApoE4 has also been implicated in poor neurological recovery after head injury, cerebral hemorrhage, and cardiac bypass surgery. [7][8][9][10][11][12] In addition, ApoE4 was suggested to act as a risk factor for bulbar-onset amyotrophic lateral sclerosis, for Pick's disease, corticobasal degeneration, and progressive supranuclear palsy (characterized by protein Tau-related cytoskeletal pathology), and for inclusion body myositis, although contradictory results have been found. [13][14][15][16][17][18][19] Epidemiological data do not provide evidence for a direct role of ApoE in central nervous system disorders, and its mechanism of action within the central nervous system is not clear. Originally, it was thought that ApoE present in neurons originated only from endocytosis. 20 -22 Numerous cell culture experiments demonstrated receptor-mediated uptake of ApoE as well as effects on neurite outgrowth and cell-morphology. [23][24][25][26][27][28][29] However, more and more evidence indicates that intraneuronal ApoE might also originate from synthesis by neurons. In situ hybridization of brain sections of transgenic mice expressing genomic fragments containing the entire human ApoE locus, including its promoter sequences, revealed expression in neurons, besides astrocytes. 30 -32 Human neuroblastoma cells were shown to synthesize both ApoE mRNA and protein. 33,34 Moreover, in situ hybridization of human brain sections conclusively demonstrated ApoE mRNA in neurons. 35 Taken together these results suggest that besides its well-known synthesis...

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Section: Discussionmentioning

confidence: 56%

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

Tesseur

Dorpe

Bruynseels

et al. 2000

The American Journal of Pathology

Self Cite

131

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“…2B). The more harmful were tau-(1-44), tau- (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44), and tau-(26-230), which reached their maximal neurotoxic effect at an MOI of 50 with only Ϸ20% of cells viable 48 h after infection. By contrast, for tau-(1-156) and tau-(45-230) the survival was 52 Ϯ 2.3% and 72 Ϯ 1.8% (n ϭ 4), respectively, at an MOI of 120.…”

Section: Resultsmentioning

confidence: 99%

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Amadoro

Ciotti

Costanzi

et al. 2006

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

225

156

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The altered function and͞or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDARmediated toxicity is postulated to play a pivotal role. extracellular-regulated kinase ͉ mitogen-activated protein kinase ͉ neurodegenerative diseases ͉ glutamate receptors ͉ Alzheimer's disease

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“…40 -45 They have tau immunoreactivity in neurons and their processes, but only one study has demonstrated immunolabeling of astrocyte-like cells at the light microscopic level. 42 Another study 43 showed aggregates of 10-to 20-nm straight filaments in myelinated spinal cord axons. The filaments were immunolabeled by antibodies to tau, tubulin, and neurofilaments.…”

Section: Discussionmentioning

confidence: 99%

Filamentous Tau in Oligodendrocytes and Astrocytes of Transgenic Mice Expressing the Human Tau Isoform with the P301L Mutation

Lin

Lewis

Yen

et al. 2003

The American Journal of Pathology

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We recently reported a transgenic mouse line (JNPL3) that expresses mutant (P301L) tau and develops neurofibrillary tangles composed of filamentous tau aggregates. Here we show that these mice have abnormal tau filaments not only in neurons, but also in oligodendrocytes and astrocytes. Similar results were detected in another transgenic line (JNPL2؉3؉) that expresses the longest human tau isoform with the P301L mutation. The ultrastructure of the tau filaments and immunoreactivity with tau and ubiquitin antibodies were similar in glia and neurons. Given similarities of the lesions in the mice to human neuronal and glial inclusions, these transgenic mice appear to be a valuable model to study pathogenesis of the neurodegenerative tauopathies.

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Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

Cited by 361 publications

References 69 publications

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Filamentous Tau in Oligodendrocytes and Astrocytes of Transgenic Mice Expressing the Human Tau Isoform with the P301L Mutation

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