SPPL2B: A NOVEL PROTEIN RELATED TO TAU PATHOLOGY IN ALZHEIMER’S DISEASE?

SPPL2b is a transmembrane protease involved in the processing of ITM2B (BRI2) and TNFα. Previously, we have shown that levels of SPPL2b were 10-fold increased in early stages of Alzheimer's disease (Braak III-IV). Moreover, we also observed co-localization of SPPL2b with phosphorylated tau. Here, we aimed to investigate the functional relation between SPPL2b and tau in cell and animal models. SPPL2b was quantified in hippocampus tissue of mice models driven by Aβ pathology (APP-PS1, n = 5) and tau pathology (P301S, n=5) as well as in HEK293 cells overexpressing P301S-Tau (n = 4). Corresponding wild-type mice and control cells were also included (n = 4–5/group). SPPL2b was 10–fold increased in the hippocampus of the mice overexpressing tau P301S (p < 0.0001) compared to wild-type. In contrast, no changes were observed in the hippocampus of APP-PS1 mice. Human cell lines overexpressing the mutated tau form also showed a strong increase in SPPL2b levels (p < 0.0001) compared to controls. results from mice and cell models suggest that SPPL2b changes are likely driven by tau pathology and not by Aβ aggregates. Whether these SPPL2b changes aid to prevent tau pathology (i.e. via lysosomal degradation) or contribute to the development of AD (i.e. neurotoxicity, tau spreading) remains to be investigated.