Are tangles as toxic as they look?

Abstract

Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated and misfolded tau protein characteristic of Alzheimer's disease and other tauopathies. Classic cross-sectional studies of Alzheimer patient brains showed associations of tangle accumulation with neuronal loss, synapse loss, and dementia, which led to the supposition that tangles are toxic to neurons. More recent advances in imaging techniques and mouse models have allowed the direct exploration of the question of toxicity of aggregated versus soluble tau and have surprisingly challenged the view of tangles as toxic species in the brain. Here, we review these recent experiments on the nature of the toxicity of tau with particular emphasis on our experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangle-bearing neurons.

Fig. 1

Some dissociation between NFT (brown) and neuronal loss (nuclei labeled blue with cresyl violet) is observed in rTg4510 mice which have substantial neuronal loss in dentate gyrus (arrows) despite very few NFT. CA1 (arrowheads) undergoes both NFT formation and neuronal loss. Scale: 500 μm

Fig. 2

Caspase activation precedes NFT formation in rTg4510 mice as modeled ion (a). Tau becomes hyperphosphorylated and mislocalized to the somatodendritic compartment. Caspases are then activated and NFT form very rapidly. Since neurons with new NFT survive at least 5 days and caspases are turned off, we postulate that NFT formation reduces the toxic soluble hyperphosphorylated tau levels in the soma allowing caspases to become deactivated preventing apoptosis. An example of caspase activation in vivo followed 24 h later by a Thioflavin S positive tangle is shown in (b). Scale: 10 μm