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

Area of Science:

• Neuroscience
• Biophysics
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid plaque accumulation.
• Amyloid beta (Aβ) peptides form these plaques, impacting brain function.
• Understanding plaque penetration is crucial for developing AD therapeutics.

Purpose of the Study:

• To investigate amyloid plaque penetrability in vivo.
• To analyze the rheology of the extracellular space (ECS) in an AD mouse model.
• To explore the relationship between ECS properties and plaque characteristics.

Main Methods:

• In vivo two-photon shadow imaging to assess plaque cell environments.
• Quantum dot and carbon nanotube tracking to measure nanoparticle diffusivity and rheology.
• Analysis of extracellular matrix composition within amyloid plaques.

Main Results:

• Cortical amyloid plaques exhibit diffusional penetrability, despite a surrounding cell ring.
• Extracellular space diffusivity is heterogeneous around and within plaques, showing increased diffusivity compared to wild-type tissue.
• Amyloid core nanoparticle density varies by plaque phenotype, and the extracellular matrix is dysregulated within plaques.

Conclusions:

• Amyloid plaque penetration is confirmed, challenging previous assumptions.
• Altered ECS rheology and diffusivity in AD mice are linked to plaque presence and extracellular matrix dysregulation.
• These findings provide critical insights for designing therapies that target Aβ plaque penetration.