INVESTIGATING THE PERIPHERAL-TO-CENTRAL TRANSMISSION OF TAU PATHOLOGY VIA SYSTEMIC ADMINISTRATION OF P301S-DERIVED BRAIN HOMOGENATES

The progression of Alzheimer's disease is characterized by the prion-like spreading of hyperphosphorylated tau (ptau) through neural networks. While central propagation is well-documented, the capacity of peripheral ptau to initiate pathology within the CNS remains an open question. Given that systemic blood transfers from tauopathy models can exacerbate neurodegeneration, we sought to determine whether peripheral exposure to other ptau-rich sources, specifically brain-derived homogenates, is sufficient to drive central seeding.
To test this, we administered brain homogenates from aged, symptomatic P301S donors to young, pre-symptomatic P301S mice via intraperitoneal injection, using animals injected with wild-type brain homogenates as controls. ELISA was used to quantify ptau markers in plasma and brain tissue, while Western blot and immunohistochemistry assays, alongside behavioral testing, were employed to determine whether the injected material can seed pathology and accelerate cognitive impairment.
Our biochemical data showed a clear increase in ptau markers within both the plasma and brain of treated mice. However, this elevation did not translate into the formation of robust pathological aggregates in the CNS, nor did it induce cognitive deficits. These findings suggest that while peripherally administered tau-rich material can cross biological barriers and raise central ptau levels, it is insufficient to trigger full-scale tauopathy in the P301S model. Such findings contrast with the pathological effects previously reported after peripheral administration of P301S-derived blood, suggesting that specific circulatory co-factors or unique systemic routes are likely necessary to drive central tau pathology from a peripheral source.