Exacerbation of Tau-Associated Pathology following Peripheral Injection of Blood from a Tauopathy Model

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. It remains unknown how tau aggregates spread beyond the central nervous system through peripheral pathways, although there is evidence that Aβ can disseminate through prion-like mechanisms in both central and peripheral routes. Tau aggregates have been detected in biological fluids and peripheral tissues in mice and humans, and current evidence suggests that tau can also propagate in a prion-like manner. Nevertheless, the role of peripheral tau aggregates in the development of tau-related disorders, including AD, is poorly understood. In this study, we explore whether peripheral administration of blood from aged P301S tau transgenic mice, a well-established tauopathy model, worsens tau-associated pathology in the brain. Young P301S mice received blood via both intraperitoneal and intravenous injections, and were evaluated through behavioral, biochemical, and histological analyses to assess brain tau-associated pathology. Our results reveal that mice receiving blood from aged tau transgenic donors exhibited significantly enhanced tau deposition in the hippocampus, along with an increased glial inflammatory response. In addition, recipient mice displayed motor impairment, indicating a worsening of neurodegenerative processes. Overall, these findings provide compelling evidence that blood from tau mice may contribute to the progression of tau-related neurodegeneration. Unraveling the mechanisms behind peripheral tau dissemination could offer novel insights into disease progression and identify potential biomarkers and therapeutic targets for AD and other tauopathies.