Decoding Amyloid Plaque Penetrability: Exploring Extracellular Space and Rheology in Plaque-rich Cortex

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