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

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.