![]() The fundamental relationship between the structure and function of biological systems implies that any dysfunction occurring under pathological conditions may be explained in terms of structural alterations. This endeavor requires integrating evidence from multiple methodological approaches used in cellular and molecular neuroscience, including structural information at the subcellular and systems biology levels. A deeper understanding of the brain structure, function and their pathological alterations is necessary to identify and develop novel therapeutic strategies. Despite global intensive research and development efforts centered on neurodegenerative diseases, there are currently no effective therapies that can revert or prevent their progression. Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), among others, are incurable brain disorders that affect millions of people worldwide, causing enormous social and economic burdens. We consider that a broader implementation of these technologies is necessary to reveal the full landscape of cellular and molecular mechanisms underlying neurodegenerative diseases. Therefore, these approaches can be readily applied to study a wide range of brain processes and pathological mechanisms with cellular and subcellular resolution in a time- and cost-efficient manner. In contrast, nanoscale imaging of expanded cells and brain tissue has been used to study the effect of protein aggregates on specific subcellular structures. ![]() Volumetric imaging of cleared intact mouse brains and large human brain samples has allowed unbiased assessment of neuropathological hallmarks. We discuss recent studies in which clearing and expansion methods have been successfully applied to study neuropathological processes in mouse models and postmortem human brain tissue. Here, we review the state-of-the-art of brain tissue clearing and expansion methods, mentioning their main advantages and limitations, and suggest their parallel implementation for circuits-to-synapses brain imaging using conventional (diffraction-limited) light microscopy -such as confocal, two-photon and light-sheet microscopy- to interrogate the cellular and molecular basis of neurodegenerative diseases. Recent advancements in brain tissue clearing and expansion methods allow unprecedented detailed imaging of the nervous system through its entire scale, from circuits to synapses, including neurovascular and brain lymphatics elements. Studying the structural alterations occurring during diseases of the nervous system requires imaging heterogeneous cell populations at the circuit, cellular and subcellular levels. 2Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.1Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
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