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Advanced Immunolabeling Method for Optical Volumetric Imaging Reveals Dystrophic Neurites of Dopaminergic Neurons in Alzheimer’s Disease Mouse Brain

Authors
Baek, Soon bongJang, JaemyungJung, Hyun JinLee, HyeyoungChoe, Young shik
Issue Date
Dec-2023
Publisher
Springer Science+Business Media, LLC, part of Springer Nature
Keywords
Neural circuits; Volumetric imaging; Alzheimer's disease; Dopamine neurons; Axon dystrophy
Citation
Molecular Neurobiology
Journal Title
Molecular Neurobiology
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/1121
DOI
10.1007/s12035-023-03823-9
ISSN
0893-7648
1559-1182
Abstract
<jats:title>Abstract</jats:title><jats:p>Optical brain clearing combined with immunolabeling is valuable for analyzing molecular tissue structures, including complex synaptic connectivity. However, the presence of aberrant lipid deposition due to aging and brain disorders poses a challenge for achieving antibody penetration throughout the entire brain volume. Herein, we present an efficient brain-wide immunolabeling method, the immuno-active clearing technique (iACT). The treatment of brain tissues with a zwitterionic detergent, specifically SB3-12, significantly enhanced tissue permeability by effectively mitigating lipid barriers. Notably, Quadrol treatment further refines the methodology by effectively eliminating residual detergents from cleared brain tissues, subsequently amplifying volumetric fluorescence signals. Employing iACT, we uncover disrupted axonal projections within the mesolimbic dopaminergic (DA) circuits in 5xFAD mice. Subsequent characterization of DA neural circuits in 5xFAD mice revealed proximal axonal swelling and misrouting of distal axonal compartments in proximity to amyloid-beta plaques. Importantly, these structural anomalies in DA axons correlate with a marked reduction in DA release within the nucleus accumbens. Collectively, our findings highlight the efficacy of optical volumetric imaging with iACT in resolving intricate structural alterations in deep brain neural circuits. Furthermore, we unveil the compromised integrity of DA pathways, contributing to the underlying neuropathology of Alzheimer’s disease. The iACT technique thus holds significant promise as a valuable asset for advancing our understanding of complex neurodegenerative disorders and may pave the way for targeted therapeutic interventions.</jats:p> <jats:p><jats:bold>Graphical Abstract</jats:bold></jats:p> <jats:p>The axonal projection of DA neurons in the septum and the NAc showed dystrophic phenotypes such as growth cone-like enlargement of the axonal terminus and aggregated neurites. Brain-wide imaging of structural defects in the neural circuits was facilitated with brain clearing and antibody penetration assisted with SB3-12 and Quadrol pre-treatment. The whole volumetric imaging process could be completed in a week with the robust iACT method. Created with <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.biorender.com/">https://www.biorender.com/</jats:ext-link>.  </jats:p>
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연구본부 (뇌발달질환 연구그룹)
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