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bioRxiv · 10.1101/2025.08.12.669914

Longitudinal three-photon imaging for tracking amyloid plaques and vascular degeneration in a mouse model of Alzheimer's disease

Stas, E.·Yang, M.·Go, M. A.·Schultz, S. R.
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Abstract

SignificanceVascular abnormalities may contribute to amyloid-beta accumulation and neurotoxicity in Alzheimers disease (AD). Monitoring vascular degeneration as AD progresses is essential. Three-photon fluorescence microscopy (3PM) enables high-resolution deep tissue imaging with minimal invasiveness and photodamage. AimThis proof-of-concept study established a longitudinal 3P imaging pipeline to quantify vascular and amyloid plaque changes in the APPNL-G-F mouse model. ApproachA cranial window allowed repeated 3P imaging at four-week intervals beginning at five weeks after surgery. Vessels labelled with Texas-Red were segmented using DeepVess, while plaques labelled with methoxy-XO4 were segmented using custom scripts. Quantitative analyses assessed vascular parameters (diameter, tortuosity, length, inter-vessel distance, total volume) and plaque metrics (radius, total volume). ResultsWe imaged the same field over 4 weeks quantifying an overall decrease in vasculature and increase in amyloid plaques between two sessions. Significant changes in vessel diameter, inter-vessel distance, as well as alterations in vessel length and plaques radius were observed. Changes in vessel tortuosity were not significant. ConclusionsWe demonstrate the potential of three-photon imaging to track vascular and amyloid-related changes in deep cortical structures. It offers a tool for studying the interplay between vascular and amyloid pathologies in AD, supporting future research into disease mechanisms and therapeutic strategies.

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Stas, E., Yang, M., Go, M. A., Schultz, S. R.. 2025-08-15. Longitudinal three-photon imaging for tracking amyloid plaques and vascular degeneration in a mouse model of Alzheimer's disease. https://doi.org/10.1101/2025.08.12.669914

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