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Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease

Abstract

The synapse has emerged as a critical neuronal structure in the degenerative process of Alzheimer disease (AD), in which the pathogenic signals of two key players — amyloid-β (Aβ) and tau — converge, thereby causing synaptic dysfunction and cognitive deficits. The synapse presents a dynamic, confined microenvironment in which to explore how key molecules travel, localize, interact and assume different levels of organizational complexity, thereby affecting neuronal function. However, owing to their small size and the diffraction-limited resolution of conventional light microscopic approaches, investigating synaptic structure and dynamics has been challenging. Super-resolution microscopy (SRM) techniques have overcome the resolution barrier and are revolutionizing our quantitative understanding of biological systems in unprecedented spatio-temporal detail. Here we review critical new insights provided by SRM into the molecular architecture and dynamic organization of the synapse and, in particular, the interactions between Aβ and tau in this compartment. We further highlight how SRM can transform our understanding of the molecular pathological mechanisms that underlie AD. The application of SRM for understanding the roles of synapses in AD pathology will provide a stepping stone towards a broader understanding of dysfunction in other subcellular compartments and at cellular and circuit levels in this disease.

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Fig. 1: The spatio-temporal dynamics of the healthy synapse.
Fig. 2: Examples of super-resolution imaging of molecules implicated in Alzheimer disease.
Fig. 3: Overview of outstanding questions that super-resolution microscopy can address.
Fig. 4: Towards a quantitative understanding of pathomechanisms in Alzheimer disease.

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Acknowledgements

The authors thank S. Lesné and V. Anggono for helpful feedback on Supplementary Fig. 1, N. M. Dixit for critical feedback on Fig. 4, R. Amor for helpful suggestions for the figure in Box 2, N. Valmas for the graphical artwork in Fig. 1a and R. Tweedale and A. Briner for critical reading of the manuscript. The authors acknowledge support by the Estate of Clem Jones, the State Government of Queensland, the Federal Government of Australia, the Australian Research Council (DP190102789) and the National Health and Medical Research Council of Australia (GNT1176326 and GNT1147569) to J.G.

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Glossary

Alzheimer disease

(AD). A progressive neurodegenerative disease that is characterized by the loss of memory and other cognitive functions.

Amyloid plaques

Major hallmark brain lesions of patients with Alzheimer disease composed of oligomeric and fibrillar forms of the amyloid-β peptide.

Neurofibrillary tangles

A critical hallmark of Alzheimer disease comprising aggregated forms of the microtubule-associated protein tau.

Super-resolution microscopy

(SRM). A collection of techniques that has overcome the diffraction limit of light and allows quantitative understanding of molecular and cellular processes with unprecedented spatio-temporal detail.

Dendritic spine

A micron-sized subcellular structure protruding from dendritic branches of neurons that houses most of the excitatory synapses in the mammalian CNS.

Synaptic plasticity

A neural activity-dependent process leading to strengthening or weakening of synaptic connections.

Presynapse

A subcompartment of axons or at the distal end of axons where synaptic vesicles fuse to release neurotransmitters.

Nanodomains

Discrete, nanometre-sized regions where diffusing molecules are trapped and concentrated.

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Padmanabhan, P., Kneynsberg, A. & Götz, J. Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease. Nat Rev Neurosci 22, 723–740 (2021). https://doi.org/10.1038/s41583-021-00531-y

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