Endogenous pathology in tauopathy mice progresses via brain networks

Abstract

Neurodegenerative tauopathies are hypothesized to propagate via brain networks. This is uncertain because we have lacked precise network resolution of pathology. We therefore developed whole-brain staining methods with anti-p-tau nanobodies and imaged in 3D PS19 tauopathy mice, which have pan-neuronal expression of full-length human tau containing the P301S mutation. We analyzed patterns of p-tau deposition across established brain networks at multiple ages, testing the relationship between structural connectivity and patterns of progressive pathology. We identified core regions with early tau deposition, and used network propagation modeling to determine the link between tau pathology and connectivity strength. We discovered a bias towards retrograde network-based propagation of tau. This novel approach establishes a fundamental role for brain networks in tau propagation, with implications for human disease.

Distinguishing microgliosis and tau deposition in the mouse brain using paramagnetic and diamagnetic susceptibility source separation

“…Our study showed significant DCS differences between the WT and Tau mouse groups in regions including the cortical amygdala, entorhinal cortex, and piriform cortical areas, that are known to be severely affected by tau pathology (Hurtado et al, 2010;Ramirez et al, 2023). Previous studies have largely reported increased paramagnetic susceptibility associated with tau pathology, in both human brain and animal models.…”

Shaping the future of preclinical development of successful disease-modifying drugs against Alzheimer's disease: a systematic review of tau propagation models

“…While some reported tau propagate in a similar manner regardless of the disease-specific inoculum [ 15 , 29 , 45 , 48 , 71 ], others showed different patterns of propagation [ 19 , 161 ]. In a nutshell, both anterograde and retrograde propagation of tau in both transgenic and WT models are related more to the strength of the connectivity of neuronal networks between the inoculation region and another brain region, rather than to the proximity of the brain region to the injection site [ 127 ].…”