Depth-resolved fiber photometry of amyloid plaque signals in freely behaving Alzheimer's disease mice

Current preclinical evaluation of Alzheimer's disease pathology in mouse models relies on post-mortem analyses, which hinders the development and optimization of therapeutic approaches. Although in vivo methods exist, monitoring amyloid plaque signals across multiple brain regions in freely behaving animals remains a significant challenge. We aim to develop an optical approach to address this challenge. We used flat and tapered optical fibers in an Alzheimer's mouse model. We first confirmed that conventional flat fiber-based photometry can detect amyloid plaque signals across multiple brain regions under anesthesia after injecting a blood-brain-barrier-permeable tracer, Methoxy-X04. The depth profile of in vivo fluorescent signals is correlated with histological signals. A machine learning approach could distinguish between in vivo fluorescent signals of mice with and without amyloid plaques. Next, after validating the feasibility of depth-resolved fiber photometry ex vivo, we chronically implanted a tapered fiber to monitor amyloid plaque signals in freely behaving mice. After injecting Methoxy-X04, fluorescent signals increased in a depth-specific manner in Alzheimer's mice, but not in their wild-type littermates. Our approach expands the capabilities of fiber photometry to monitor molecular pathologies, such as amyloid plaques, even in a freely behaving condition.