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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

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

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