Figure 9.

Genetic inactivation of PI3Kδ increases survival and rescues spatial learning and memory of APP/PS1 mice. A, APP/PS1 transgenic mice (n = 131) present with a pronounced premature mortality that is ameliorated by inactivating PI3Kδ (p < 0.0001). Whereas the lethality was 42.7% in the APP/PS1 mice at the 210 d time point, in APP/PS1/δ^D910A animals (n = 100) it was reduced to 3%. B, Representative images of swimming tracks for mice of different genotypes on days 1, 3, and 5 of the learning phase of the Morris water maze. C, Learning acquisition plot measured as the time taken for mice to reach the submerged platform (latency) during the learning phase (daya 1, 3, and day 5). D, Latency to target the platform area during the probe test. E, Number of platform crossings during the probe test. F, Schematic diagram summarizing a model for the regulation of APP and TNFα trafficking by PI3Kδ in neurons and microglia. PI3Kδ is involved in the trafficking of APP and TNFα by controlling the formation of TGN-derived cargoes in neurons and microglia, respectively. By pharmacological modulation of PI3Kδ activity using CAL-101, the release of neuronal Aβ and microglial TNFα can be attenuated, reducing the extent of Aβ plaque formation and neuroinflammation. Data are displayed as mean ± SEM of n = 10 animals aged 6.5 months old per genotype, one-way ANOVA, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.001.