Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation
<p>Abstract</p> <p>Background</p> <p>Although the mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ<sub>42</sub>. The 5XFAD mouse model of amyloid deposition expresses five familial AD (FAD)...
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| Format: | Article |
| Language: | English |
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BMC
2013-01-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://www.molecularneurodegeneration.com/content/8/1/2 |
| _version_ | 1819122270525718528 |
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| author | Eimer William A Vassar Robert |
| author_facet | Eimer William A Vassar Robert |
| author_sort | Eimer William A |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Although the mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ<sub>42</sub>. The 5XFAD mouse model of amyloid deposition expresses five familial AD (FAD) mutations that are additive in driving Aβ<sub>42</sub> overproduction. 5XFAD mice exhibit intraneuronal Aβ<sub>42</sub> accumulation at 1.5 months, amyloid deposition at 2 months, and memory deficits by 4 months of age.</p> <p>Results</p> <p>Here, we demonstrate by unbiased stereology that statistically significant neuron loss occurs by 9 months of age in 5XFAD mice. We validated two Aβ<sub>42</sub>-selective antibodies by immunostaining 5XFAD; BACE1<sup>−/−</sup> bigenic brain sections and then used these antibodies to show that intraneuronal Aβ<sub>42</sub> and amyloid deposition develop in the same regions where neuron loss is observed in 5XFAD brain. In 5XFAD neuronal soma, intraneuronal Aβ<sub>42</sub> accumulates in puncta that co-label for Transferrin receptor and LAMP-1, indicating endosomal and lysosomal localization, respectively. In addition, in young 5XFAD brains, we observed activated Caspase-3 in the soma and proximal dendrites of intraneuronal Aβ<sub>42</sub>-labeled neurons. In older 5XFAD brains, we found activated Caspase-3-positive punctate accumulations that co-localize with the neuronal marker class III β-tubulin, suggesting neuron loss by apoptosis.</p> <p>Conclusions</p> <p>Together, our results indicate a temporal sequence of intraneuronal Aβ<sub>42</sub> accumulation, Caspase-3 activation, and neuron loss that implies a potential apoptotic mechanism of neuron death in the 5XFAD mouse.</p> |
| first_indexed | 2024-12-22T06:49:47Z |
| format | Article |
| id | doaj.art-99caa40ffd3442c9b80142319f937f38 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-22T06:49:47Z |
| publishDate | 2013-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-99caa40ffd3442c9b80142319f937f382022-12-21T18:35:12ZengBMCMolecular Neurodegeneration1750-13262013-01-0181210.1186/1750-1326-8-2Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activationEimer William AVassar Robert<p>Abstract</p> <p>Background</p> <p>Although the mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ<sub>42</sub>. The 5XFAD mouse model of amyloid deposition expresses five familial AD (FAD) mutations that are additive in driving Aβ<sub>42</sub> overproduction. 5XFAD mice exhibit intraneuronal Aβ<sub>42</sub> accumulation at 1.5 months, amyloid deposition at 2 months, and memory deficits by 4 months of age.</p> <p>Results</p> <p>Here, we demonstrate by unbiased stereology that statistically significant neuron loss occurs by 9 months of age in 5XFAD mice. We validated two Aβ<sub>42</sub>-selective antibodies by immunostaining 5XFAD; BACE1<sup>−/−</sup> bigenic brain sections and then used these antibodies to show that intraneuronal Aβ<sub>42</sub> and amyloid deposition develop in the same regions where neuron loss is observed in 5XFAD brain. In 5XFAD neuronal soma, intraneuronal Aβ<sub>42</sub> accumulates in puncta that co-label for Transferrin receptor and LAMP-1, indicating endosomal and lysosomal localization, respectively. In addition, in young 5XFAD brains, we observed activated Caspase-3 in the soma and proximal dendrites of intraneuronal Aβ<sub>42</sub>-labeled neurons. In older 5XFAD brains, we found activated Caspase-3-positive punctate accumulations that co-localize with the neuronal marker class III β-tubulin, suggesting neuron loss by apoptosis.</p> <p>Conclusions</p> <p>Together, our results indicate a temporal sequence of intraneuronal Aβ<sub>42</sub> accumulation, Caspase-3 activation, and neuron loss that implies a potential apoptotic mechanism of neuron death in the 5XFAD mouse.</p>http://www.molecularneurodegeneration.com/content/8/1/2Intraneuronal Aβ<sub>42</sub>5XFADAlzheimer’s diseaseAmyloid-βCaspase-3Neuron lossApoptosis |
| spellingShingle | Eimer William A Vassar Robert Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation Molecular Neurodegeneration Intraneuronal Aβ<sub>42</sub> 5XFAD Alzheimer’s disease Amyloid-β Caspase-3 Neuron loss Apoptosis |
| title | Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation |
| title_full | Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation |
| title_fullStr | Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation |
| title_full_unstemmed | Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation |
| title_short | Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ<sub>42</sub> accumulation and Caspase-3 activation |
| title_sort | neuron loss in the 5xfad mouse model of alzheimer s disease correlates with intraneuronal aβ sub 42 sub accumulation and caspase 3 activation |
| topic | Intraneuronal Aβ<sub>42</sub> 5XFAD Alzheimer’s disease Amyloid-β Caspase-3 Neuron loss Apoptosis |
| url | http://www.molecularneurodegeneration.com/content/8/1/2 |
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