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The Journal of Neuroscience, January 23, 2008, 28(4):862-867; doi:10.1523/JNEUROSCI.3072-08.2008

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Brief Communications
In Vivo Imaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Tara L. Spires-Jones,¹ Alix de Calignon,¹ Toshifumi Matsui,¹ Cindy Zehr,³ Rose Pitstick,⁴ Hai-Yan Wu,¹ Jennifer D. Osetek,¹ Phillip B. Jones,^1,2 Brian J. Bacskai,¹ Mel B. Feany,⁵ George A. Carlson,⁴ Karen H. Ashe,⁶ Jada Lewis,³ and Bradley T. Hyman¹

¹MassGeneral Institute for Neurodegenerative Disease and ²Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, ³Neurogenetics, Neurotransgenics and Neuropathology Laboratories, Mayo Clinic, Jacksonville, Florida 32224, ⁴McLaughlin Research Institute, Great Falls, Montana 59405, ⁵Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and ⁶Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Correspondence should be addressed to Bradley T. Hyman, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street, Charlestown, MA 02129. Email: bhyman{at}partners.org

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.

Key words: Alzheimer's; neurofibrillary tangle; caspase; apoptosis; multiphoton imaging; tauopathy

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Received July 6, 2007; revised Oct. 18, 2007; accepted Nov. 16, 2007.

Correspondence should be addressed to Bradley T. Hyman, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street, Charlestown, MA 02129. Email: bhyman{at}partners.org

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