Abstract

Studying the structural alterations occurring during diseases of the nervous system requires imaging heterogeneous cell populations at the circuit, cellular and subcellular levels. 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. 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. 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. Volumetric imaging of cleared intact mouse brains and large human brain samples has allowed unbiased assessment of neuropathological hallmarks. In contrast, nanoscale imaging of expanded cells and brain tissue has been used to study the effect of protein aggregates on specific subcellular structures. 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. We consider that a broader implementation of these technologies is necessary to reveal the full landscape of cellular and molecular mechanisms underlying neurodegenerative diseases.

Highlights

  • 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

  • Despite global intensive research and Tissue Clearing and Expansion in Neurodegeneration development efforts centered on neurodegenerative diseases, there are currently no effective therapies that can revert or prevent their progression

  • This may seem over-simplistic for a highly complex organ such as the brain structural changes in specific cell types underlie almost every long-term brain function under a wide range of physiological and pathological conditions, including learning, memory, acquisition of motor skills, emotional and stress responses, neurodevelopmental and neuropsychiatric disorders -including addictions, inflammation, aging, and neurodegeneration

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Summary

Introduction

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. Recent studies have applied tissue clearing methods to evaluate some of these neuropathological hallmarks in large human brain samples and entire brains from transgenic mouse models.

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