[P1–182]: PHOSPHATASE ACTIVITY DURING SLEEP/WAKE CYCLES REGULATES APP PROCESSING AND BRAIN ISF AMYLOID‐β LEVELS

a Meso Scale Discovery SECTOR 6000. Results:All following results are presented as the average of day 100 and 200 6 standard error. Variation in absolute biomarker concentrations was within acceptable limits for Ab (7.9%CV60.5), but high for Ttau (16.8%CV61.8). Inductions of the same cell line displayed variation similar to that between cell lines. However, ratios of Ab peptides were highly consistent over time (3.4%CV60.3). All control lines secreted Ab in similar ratios (Ab42:40 1⁄4 0.16<0.1, Ab42:381⁄4 0.46<0.1, Ab40:381⁄4 4.06<0.1). Versus controls, APP cells demonstrated increased Ab42:40 (0.26<0.1), slightly increased Ab42:38 (0.56<0.1), and decreased Ab40:38 (2.56<0.1). PSEN1 intron 4 deletion cells had increased Ab42:40 (0.26<0.1), increased Ab42:38 (1.26<0.1) and increased Ab40:38 (5.36<0.1). PSEN1 M139V cells had increased Ab42:40 (0.26<0.1), increased Ab42:38 (0.96<0.1), and slightly increased Ab40:38 (4.46<0.1). Ab:T-tau ratios were highly variable (23.8% CV6<1.8) and yielded little distinction between cell lines, although tau decreased in relation to Ab over the time course. Conclusions: Human cortical neurons harbouring specific fAD mutations all increased Ab42:40 secretion into the extracellular space (by approximately two-fold) versus controls. The Ab40:38 ratio distinguished well between different mutations, and may shed light on the question of g-secretase cleavage pathways for the generation of Ab.