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• W2100026237 abstract "Based largely on evidence from post-mortem examination of brain tissue, it is thought that abnormal fibrillar deposits of tau protein — which when functioning normally acts to stabilize microtubules — cause apoptosis and neurodegeneration in Alzheimer's disease and tau-related frontotemporal dementia. Now in vivo multiphoton imaging of these neurofibrillary tangles in transgenic mice overexpressing a human tau gene reveals a rather different scenario. Caspase activation — a known marker for apoptosis — is the first abnormality observed, preceding tangle formation by hours to days. Rather than suffering cell death, neuronal cells bearing tangles appear to be long-lived, and caspase activity subsides. It is therefore possible that soluble tau, rather than fibrillar tau, is causing neurodegeneration. As to the relevance of this work to the value of 'tangle-busting' drugs in countering neurodegeneration, much depends on whether neurofibrillary tangles are a protective factor, an irrelevance to the disease, or are associated with slow-acting neurotoxicity. Fibrillar deposits of tau protein (neurofibrillary tangles) are thought to cause neuronal death in patients with Alzheimer's disease, and tau-related frontotemporal dementia. Here, however, the opposite has been found: the activation of executioner caspase enzymes occurs first, preceding tangle formation by hours to days. Tangle-bearing neurons seem to be long-lived, indicating that tangles might be 'off pathway' to acute neuronal death. Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death1,2, severe cytological abnormalities3, and markers of caspase activation and apoptosis4,5,6, leading to the idea that tangles cause neurodegeneration in Alzheimer’s disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are ‘off pathway’ to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration." @default.
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• W2100026237 date "2010-03-31" @default.
• W2100026237 modified "2023-10-17" @default.
• W2100026237 title "Caspase activation precedes and leads to tangles" @default.
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• W2100026237 doi "https://doi.org/10.1038/nature08890" @default.
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