FIGURE 7.

TWS119 triggers mitochondrial respiration in the AD mouse cortex. A, 2P‐FLIM imaging of the APP^SAA/+ mouse cortex through an open‐skull window before and after topical application of TWS119. An increase in a₂% was observed for several minutes indicating upregulation of mitochondrial activity. Statistical analyses were performed using Student two‐tailed paired t test. Three animals were used in these experiments. B, MP‐PAM imaging of APP^SAA/+ mouse cortex through an open‐skull window before and 80 minutes after a topical application of TWS119. A small decrease in blood oxygenation of the cortical arteries and veins was observed but did not reach statistical significance. Still, there was a significant increase in the overall OEF. The bar graphs show the quantification of three independent experiments. Statistical analyses were performed using Student two‐tailed unpaired t test. Error bars represent ± standard error of the mean. C, Model for NiMA regulation by GSK3β in vivo in the brain:(C.1) In normal physiological conditions insulin and amino acids stimulate lysosomal mTORC1 ⁷ by a mechanism involving inhibition of GSK3β. Then, mTORC1‐mediated phosphorylation of SOD1 at T40, ¹⁰ triggers mitochondrial respiration. (C.2) Insulin‐mediated inhibition of GSK3β is blocked by AβOs, decreasing mTORC1 activity on lysosomes and stimulating it instead at the plasma membrane, where mTORC1 kinase activity triggers CCR, a frequent prelude to cortical neuron death in AD. (C.3) Pharmacological treatments that block AβO‐induced activation of GSK3β might restore normal lysosomal mTORC1 activity in AD. 2P‐FLIM, two‐photon fluorescence lifetime imaging; AD, Alzheimer's disease; APP^SAA/+, heterozygous amyloid precursor protein knock‐in; CCR, cell cycle re‐entry; GSK3β, glycogen synthase kinase 3; MP‐PAM, multi‐parametric photoacoustic microscopy; NiMA, nutrient‐induced mitochondrial activity; OEF, oxygen extraction fraction; SOD1, superoxide dismutase 1.