Nanoscale Structural and Immunological Remodeling of the Primo Vascular System in Alzheimer’s Disease: Mast Cell Activation Along the Gut–Brain Axis

The primo vascular system (PVS) is a fine-scale circulatory network composed of nanoscale tissues that are closely associated with biological signal transmission pathways, such as the gut-brain axis, and that harbor immune and regenerative cells. Mast cells (MCs), critical mediators of gut-brain axis communication, have been implicated in the pathogenesis of Alzheimer's disease (AD). Characterized by a high MC density, the PVS is increasingly recognized as a potential modulator of immune responses and tissue regeneration. However, its pathological alterations in neurodegenerative conditions remain poorly understood. This study aimed to investigate the nanoscale structural and immunological characteristics of the organ surface and meningeal PVS (OS-PVS and M-PVS) in APP/PS2 transgenic mice, a well-established model of AD. Behavioral testing in APP/PS2 mice confirmed cognitive impairments characteristic of AD. Atomic force microscopy revealed irregular alignment of primo subvessels and interstitial spaces, along with increased surface roughness and loss of spatial periodicity. Scanning electron microscopy showed a significant increase in the density and diameter of primo pores, as well as reduced fiber structure diameter, suggesting ultrastructural remodeling. Toluidine blue and immunofluorescence staining demonstrated elevated MC density and degranulation ratio within the PVS. These findings suggest that the OS-PVS and M-PVS undergo coordinated nanoscale structural and immunological remodeling in AD, reflecting shared pathological features within the PVS. MC activity within the PVS may contribute to the neuroimmune dysregulation underlying disease progression, supporting its role as an anatomical conduit for immune communication along the gut-brain axis.