Caspase activation precedes and leads to tangles

Tangled tau: friend or foe? 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.