Hyperphosphorylated aggregations of microtubule-associated protein tau are associated with several neurodegenerative diseases collectively classified under the term tauopathy.  While prior studies have analyzed immunotherapy-like-approaches in transgenic mice expressing human tau, the use of human antibodies in transgenic mice fails to discriminate the injected tau seeds and the endogenously expressed Tau and leaving the exact mechanism of tau immunotherapies unknown. To gain insights into the mechanism of tau immunotherapies, we will use a mouse tau antibody (mTau8) to specifically target the endogenous mouse tau without affecting the activity of human tau seeds in vivo. Evaluating the effectiveness of this treatment in the mouse brain and in mouse primary neuron models will elucidate the mechanism by which an immunotherapy-like-antibody treatment affects disease progression at a clinically relevant post-diagnosis timepoint. Our findings demonstrate the antibody’s highly selective properties to mouse tau, its capabilities in entering the cerebrospinal fluid by bypassing the blood-brain-barrier,  and its ability to decrease tau pathology on the scale of 83.2-91.2% at a 4.5-month timepoint in mouse models. Analysis of these findings, with the mouse brain connectome in mind, reveals a “global” reduction of tau reduction and suggests a mechanism of reduction independent of the cell to cell spreading of pathological tau species. Experimental results in vivo will confirm mTau8’s capabilities in reducing tau pathology and live imaging of the cells treated with fluorescently labeled human ADphfs and labeled mTau8 shows statistically significant colocalization.