Advanced imaging of tau pathology in Alzheimer Disease: New perspectives from super resolution microscopy and label‐free nanoscopy

Abstract

Alzheimer's disease (AD) is the main cause of dementia in the elderly population. Over 30 million people worldwide are living with dementia and AD prevalence is projected to increase dramatically in the next two decades. In terms of neuropathology, AD is characterized by two major cerebral hallmarks: extracellular β-amyloid (Aβ) plaques and intracellular Tau inclusions, which start accumulating in the brain 15-20 years before the onset of symptoms. Within this context, the scientific community worldwide is undertaking a wide research effort to detect AD pathology at its earliest, before symptoms appear. Neuroimaging of Aβ by positron emission tomography (PET) is clinically available and is a promising modality for early detection of Aβ pathology and AD diagnosis. Substantive efforts are ongoing to develop advanced imaging techniques for early detection of Tau pathology. Here, we will briefly describe the key features of Tau pathology and its heterogeneity across various neurodegenerative diseases bearing cerebral Tau inclusions (i.e., tauopathies). We will outline the current status of research on Tau-specific PET tracers and their clinical development. Finally, we will discuss the potential application of novel super-resolution and label-free techniques for investigating Tau pathology at the experimental level and their potential application for AD diagnosis. Microsc. Res. Tech. 79:677-683, 2016. © 2016 Wiley Periodicals, Inc.

Molecular Imaging of Tau Protein: New Insights and Future Directions

“…Last, the incomplete labeling could lead to spurious results; this represents a very critical point for the study of in vitro aggregation of misfolded proteins in particular (Cosentino et al, 2019). It is likely that in the future a refinement of labeling methods for SRM combined with label-free microscopy (Schierle et al, 2016) could allow these problems to be overcome. The development of selective probes for diagnostic purposes is a very active field of research.…”

“…SRM is particularly useful in that they allow to monitor protein dynamics in situ, both in fixed and living specimens, opening the way for the study of the initial steps of protein aggregation and their dynamics over time. Works examining these aspects at subcellular level are starting to become available (Schierle et al, 2016;Lu et al, 2020); however, some technical aspects such as long-term imaging, fluorophore bleaching, and specimen thickness are still major obstacles that need to be overcome (see ''Conclusion and Future Directions'' section).…”

Super-resolving Microscopy in Neuroscience

“…Similar to Aß pathology, SRM has been applied to gain closer insights into tau pathomechanisms and cellular propagation. 411 Fluorescent lifetime imaging in combination with two-color dSTORM with reporter fluorophores of human tau 40 and K18 constructs revealed uptake of monomeric tau in a neuronal cell line followed by aggregation of endogenous tau and infection of neighboring cells. 412 Super-resolved lifetime imaging of intracellular tau aggregation and clustering was achieved with SIM and fluorescent labeled K18 tau 413 (Figure 17).…”

Tissue Clearing and Expansion Methods for Imaging Brain Pathology in Neurodegeneration: From Circuits to Synapses and Beyond

“…For instance, STORM and STED SRM have been applied to study the aggregation states of Huntingtin exon 1, including the formation of inclusion bodies and other fibrillary species in living and fixed cells ( Duim et al, 2014 ; Sahl et al, 2016 ), while SIM SRM has been used to study the interaction of mHTT aggregates with transcription factors ( Li et al, 2016 ), which could mediate altered gene expression in HD ( Giralt et al, 2012 ). Different optical SRM approaches have helped to image both Aβ and tau aggregates in vitro and in cellular models ( Pinotsi et al, 2016 ; Schierle et al, 2016 ), while STED SRM was used to image immunolabelled tau filaments in postmortem AD brain sections (50 μm) at ∼80 nm resolution ( Benda et al, 2016 ). A recent study used STED SRM to identify disruption of the lamin nucleoskeleton in a Drosophila model of tau pathology and in human postmortem AD brain tissue, suggesting that lamin dysfunction contributes to tau-mediated neurodegeneration ( Frost et al, 2016 ).…”