In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Abstract

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.

Aging Analysis Reveals Slowed Tau Turnover and Enhanced Stress Response in a Mouse Model of Tauopathy

“…The fact that tau over-expression may be facilitating stress protein expression further implicates their role in facilitating pathogenesis. If heat shock proteins are facilitating filament formation, in light of recent evidence from our group and others suggesting that the tangles themselves might not be toxic, but rather soluble intermediates, 8,12,17 then it still is possible that chaperones are protective. While, it has yet to be definitively demonstrated how chronically elevated expression of stress proteins will affect the neurodegenerative disease process in the mammalian brain, these data certainly are suggestive that they are intimately involved.…”

“…9 -11 These mice have also been used to address very topical questions for the field such as the role of caspase cleavage of tau in tangle formation. 12,13 A large repertoire of immunological agents is available for various tau species, particularly those that recognize distinct phospho-tau species, each of which has unique properties; however, only a handful of these have been investigated in this model. In our current report, we endeavored to extensively evaluate the biochemical and histological properties of these distinct tau species cross-sectionally.…”

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

“…is the hallmark of many neurodegenerative diseases, these types of pathologies do not correlate well with neuronal loss or dysfunction in animal models of disease. For example, in the rTg4510 tau transgenic mice, neurons with tau tangle structures are longer lived (4,67). This same model displays cognitive recovery when tau is suppressed, despite continued tangle formation (5,46).…”

The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities

“…Even more convincing then this study, are the recent studies coming out of Bradley Hyman's group using multiphoton microscopy, a technique that allows one to detect caspase activation in the living brain and follow this activation over several days. Using this powerful technique, Spires-Jones et al were able to detect active caspases within tangle-bearing neurons in the rTg4510 mouse model of tauopathy [25]. They have been able to extend these findings by showing that even though caspases are activated with NFT-bearing neurons, these neurons do not immediately die, but exhibit significant loss of membrane integrity as indicated by the presence of propidium iodide labeling [26].…”