Author

T. Malm

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Open access Sep 2026

Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology

Alzheimer’s disease (AD) pathology involves amyloid deposition, reactive gliosis, and localized tissue alterations that coexist within the same brain regions, creating heterogeneous microstructural environments within individual imaging voxels. Conventional diffusion MRI averages these environments into aggregate measures, potentially obscuring their distinct contributions. Frequency-dependent multidimensional MRI (ωMD-MRI) resolves distributions of water components with different diffusion length scales, anisotropies, and relaxation properties, providing sensitivity to microstructural restriction, heterogeneity, and shape-size correlations within a voxel. Whether these measurements reveal microstructural complexity associated with AD pathology remains unclear. Here, we performed ωMD-MRI on ex vivo brain specimens from approximately 8-month-old 5xFAD and wild-type mice and interpreted the imaging findings alongside complementary histology. ωMD-MRI revealed widespread but spatially nonuniform differences between 5xFAD and wild-type brains. Measurements sensitive to microstructural restriction, heterogeneity, and shape-size correlations consistently indicated greater microstructural heterogeneity in 5xFAD brains, with the most prominent differences in the hippocampal formation and major cerebral white matter tracts. Complementary qualitative histology demonstrated extensive amyloid deposition and glial activation in affected regions, while overall cytoarchitecture and myelin organization remained largely preserved. Thus, the ωMD-MRI abnormalities occurred in tissue characterized by multiple coexisting pathological and relatively preserved microstructural environments rather than widespread structural degeneration. These findings demonstrate that ωMD-MRI can reveal the spatial and microstructural heterogeneity associated with amyloid pathology and provide a more comprehensive characterization of AD-related tissue alterations.

P. Or, Maxime Yon, Omar Narvaez et al. · bioRxiv · 0 citations

Open access Aug 2026

Mechanical Activation of Piezo1 by Virus-like Nanospikes to Potentiate STING-driven Macrophage Reprogramming

Mechanotransduction plays a fundamental role in regulating immune cell function, yet how engineered virus-like nanospikes engage mechanosensitive signaling pathways to modulate innate immunity remains poorly understood. Here, we report virus-like nanotopography as a previously unrecognized regulator of Piezo1-mediated mechanotransduction in macrophages using virus-like mesoporous silica nanoparticles (VLPSi) with tunable rigid nanospike lengths. We demonstrate a direct structure–activity relationship between nanospike geometry and Piezo1-dependent Ca²+ influx, with longer nanospikes inducing significantly greater intracellular Ca²+ signaling. Building on this mechanistic insight, we developed biomimetic cancer cell membrane (CM)-coated, MSA-2-loaded VLPSi nanoparticle (CM/MSA-2@VLPSi) and investigate the combination of nanospikes-activated Piezo1 with STING signaling and CM antigens presentation in macrophage immune reprogramming. The resulting biomimetic nanoparticles robustly activate the STING–TBK1–IRF3/NF-κB axis, increase IFN-β and pro-inflammatory cytokine production, and promote macrophage polarization toward M1 phenotype in a spike-length-dependent manner. Collectively, the present study provides a biomimetic strategy for enhancing the M1 polarization of macrophage through the coordinated regulation of mechanical, inflammatory, and antigenic signals.

Jiajia Wang, Minna Sivonen, E. Batnasan et al. · bioRxiv · 0 citations