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

## TL;DR

This study uses advanced imaging to map the extracellular space around amyloid plaques in Alzheimer's disease, revealing changes in diffusion and structure that could impact drug delivery.

## Contribution

The study introduces novel insights into the diffusivity and rheology of the extracellular space in amyloid plaque-rich regions of Alzheimer's disease.

## Key findings

- Amyloid plaques are surrounded by a dense cell ring but allow diffusional penetration into the core.
- Extracellular space diffusivity is higher in and around plaques compared to normal tissue.
- Altered extracellular matrix within plaques may explain the observed diffusivity changes.

## 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.

The extracellular space and diffusion around amyloid plaques are examined using shadow imaging and single‐particle tracking. Increased diffusivity is found near plaques, extracellular matrix alterations, and plaque core penetrability that varies with amyloid phenotype.