Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by the accumulation of Aβ and Tau proteins. While many animal models primarily focus on Aβ, this study centers on characterizing a tauopathy model, the PS19 model (B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J), to explore the pathological role of tau in AD.36 PS19 and 24 non-carrier mice (NCAR) were followed from 12 to 50 weeks, assessing locomotor, behavior, and memory activity, neurodegeneration, neuroinflammation, blood-brain barrier (BBB) integrity, cerebral glucose metabolism, and neurodegenerative progression biomarkers, with follow-ups every 4, 8, and 12 weeks.PS19 mice exhibited motor impairments, including reduced rotarod latency in constant-speed (group factor, GF, p=0.0004) and acceleration tests (GF, p=0.0113), diminished maximum speed in the open field test (GF, p <0.0001), and increased neurodegeneration in the Hind-limb clasping test, along with reduced weight (both GF, p<0.0001). Behavior showed an increased trend in hyperactivity, risk conduct, and memory impairment. Neuroimaging studies revealed decreased cortical (GF, p=0.0023) and hippocampal volumes (GF, p=0.0128), lower water content (Cx GF, p=0.001 and HC GF, p=0.007), and Fe2+ levels (Cx GF, p=0.0255 and HC GF, p=0.0033) in both regions. PS19 mice also displayed signals of BBB alteration and reduced glucose metabolism. Biomarker analysis demonstrated higher levels of circulating CD34+ cells at 50 weeks (p= 0.0004), and from week 28 onwards, an increasing trend in pTau and neuroinflammation compared to NCAR.In conclusion, the PS19 model emerges as a valuable preclinical tool for assessing therapeutic and diagnostic targets in AD, especially in the context of tau pathology.