Decoding Amyloid Plaque Penetrability: Exploring Extracellular Space and Rheology in 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. 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. Competing Interest Statement E.B. is the Chief Scientific Officer of Motac Neuroscience Ltd. All1045 other authors declare no competing interests Footnotes ↵* Co-Corresponding authors. Funding: This study received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant agreement No. #951294 to EB, UVN, LC, and LG), the Human Frontier Science Program (Grant No. RGP0036/2020 to UVN) and financial support from the French government in the framework of the University of Bordeaux’s IdEx “Investments for the Future” program/GPR BRAIN_2030.