Blood brain barrier damage in a mouse model of frontotemporal dementia

Background Clinical evidence supports a major contribution of vascular insufficiency to the development of tauopathies. Interestingly, observations in patients with Fronto‐Temporal Demetia (FTD) highlighted microvascular changes predominantly within the areas affected by neuronal pathology. Further, data in animal model demonstrated that Tau‐P301L induces neurovascular dysfunctions independent of neurodegeneration, suggesting that cells of the Blood Brain Barrier (BBB) may represent a novel therapeutic target. However, the molecular mechanisms of vascular insufficiency in FTD remain elusive. Method To establish the pathological relationship between BBB alteration and FTD progression, we used JNPL3 mice, which express human Tau‐P301L mutation, and wild‐type (WT) controls. We assessed their memory at 5, 10 and 15 months using the Radial‐Arm‐WaterMaze (RAWM) and Y‐maze and their white matter integrity by MRI. We assessed Tau pathological changes (hyperphosphorylation and aggregation) and vascular alterations by WB and RT‐PCR. In addition, to determine the causal link between Tau and BBB damage we assessed viability of brain microvascular endothelial cells (BMECs) exposed toTau oligomers (oP301L) in vitro. Result Compared to WT, white matter integrity is significantly compromised as early at 5 months in JNPL3 mice, when modest alterations in cognition also appear, while more pronounced memory deficits occur at 10 months. pTau‐(199/202) and IgG extravasation increase over time starting at 5 months and Claudin5 (CLND5), the most enriched tight‐junction protein in BMECs, is reduced in JNPL3 at 15 months. In addition, the mRNA for ICAM‐1(Intercellular Adhesion Molecule‐1) is upregulated already at 5 months in JNPL3 mice, indicating that BMECs acquired a proinflammatory phenotype. Further, oP301L reduced significantly BMECs viability in vitro after 24h. Conclusion Our data demonstrate that endothelial alteration occur at early stages of disease in JNPL3 mice. Based on these we hypothesize that: 1) Tau deposition in blood vessel might be an early event that precedes neuronal loss; 2) cognitive deficits arise from the toxic effects of oTau both on neurons and endothelial cells, thus suggesting that targeting both cells might be more effective to slow down disease’s progression.