Abstract

Aims

Super-resolution (SR) microscopy methods enables the study of the brain on the nanoscale. Our aim is to combine array tomography (AT) and different SR techniques to investigate neuropathological traits that fall under the limits of conventional microscopy.

Methods

We combined AT, a method based on the 3D reconstruction of ultrathin consecutive sections, and Stimulated Emission Depletion (STED) microscopy or Stochastic Optical Reconstruction Microscopy (STORM) in human Alzheimer‘s disease (AD) and dementia with Lewy bodies (DLB) tissue samples.

Results

Here we show different applications to human neurodegenerative disease. First, we combined AT and STED microscopy to study synaptic p-α-synuclein in dementia with Lewy bodies and reported small aggregates in pre- and post-synaptic compartments. Second, we combined AT and STORM to study single synapses and the pathological accumulation of phosphorylated tau as an early event prior to neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD). Finally, we studied the nanoscale architecture of human amyloid plaques in AD combining AT and STED microscopy. This technology revealed a dense core with a peripheral halo and provided evidence of higher levels of small Aβ species in autosomal dominant Alzheimer’s disease (ADAD) compared to sporadic AD (SAD) cases.

Conclusions

SR techniques show high potential to unravel pathological traits undetectable using conventional microscopy techniques that may inform about key pathophysiological processes in neurodegenerative diseases.

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