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Light sheet fluorescence microscopy ( LSFM) has emerged as a powerful tool in preclinical obesity target and drug discovery, as LSFM allows for ex vivo whole-organ labelling and quantitative 3D imaging in the intact organ, including the brain, at cellular resolution

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However, this review also critically evaluates alternative explanations for the translational gap, including limited central nervous system penetration, insufficient pharmacodynamic target engagement, a mismatch between the drugs metabolic mechanisms and the amyloid-driven pathology of established AD, and the inherent limitations of preclinical models