Neurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer’s pathology

SUMMARY

A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer’s disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer’s donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer’s.

In brief

Zwang et al. used two-photon microscopy to track neurofibrillary tangle (NFT) formation and neuron loss in model mice. They observed that neurons with NFTs died less frequently than neurons without NFTs. Dying neurons could also be identified by local cortical microstructure changes, providing a method to identify susceptible populations.

Graphical Abstract