Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 4, Pages 862-867Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3072-08.2008
Keywords
Alzheimer's; neurofibrillary tangle; caspase; apoptosis; multiphoton imaging; tauopathy
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Funding
- NIA NIH HHS [AG26249, P30 AG062421, R01 AG026252, R01 AG008487, T32 AG000277, AG00277, R01 AG026249, R01-AG26252, AG08487, P50 AG005134] Funding Source: Medline
- NIBIB NIH HHS [R01 EB000768, EB00768] Funding Source: Medline
- NINDS NIH HHS [R01 NS046355, R01-NS46355] Funding Source: Medline
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Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.
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