Nanoscopic Mapping of the Extracellular Space in Amyloid Plaque‐rich Cortex

Abstract A hallmark of Alzheimer's disease (AD) is the accumulation of amyloid plaques, primarily composed of misfolded amyloid β (Aβ) peptides. Complementary high‐resolution imaging techniques are employed to investigate the plaque penetrability and the extracellular space (ECS) rheology in a mouse model of AD. Two‐photon shadow imaging in vivo confirms that a dense ring of cells surrounds cortical amyloid plaques but highlights the diffusional penetrability of the amyloid core. Quantum dot tracking unveils that ECS diffusional parameters are heterogeneous in and around plaques, with an elevated diffusivity within and around plaques compared to wild‐type‐tissue. The amyloid core shows low nanoparticle density, varying by plaque phenotype. Carbon nanotube tracking confirms these altered local rheological properties at the level of the whole cortex of AD mice. Finally, the extracellular matrix is found to be dysregulated within the amyloid plaque, which may account for the observed alterations in diffusivity. This study provides fresh insights for understanding Aβ plaque penetration, a prerequisite for therapeutic development.