In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons.
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.
Spires-Jones
Tara L
TL
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
de Calignon
Alix
A
Matsui
Toshifumi
T
Zehr
Cindy
C
Pitstick
Rose
R
Wu
Hai-Yan
HY
Osetek
Jennifer D
JD
Jones
Phillip B
PB
Bacskai
Brian J
BJ
Feany
Mel B
MB
Carlson
George A
GA
Ashe
Karen H
KH
Lewis
Jada
J
Hyman
Bradley T
BT
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism / Q000502:physiology
D016875:tau Proteins; D020169:Caspases