Dietary magnesium ions block the effects of nutrient deficiency on inducing the formation of LC3B autophagosomes and disrupting the proteolysis of autolysosomes to degrade β-amyloid protein by activating cyclooloxygenase-2 at tyrosine 385

[Display omitted] •As an important mineral nutrient, Mg2+ inhibits the activity of COX-2 via mTORC1.•By nutrient deprivation, COX-2 activation induces formation of LC3B autophagosomes.•Mg2+ disrupts the formation of LC3B autophagosomes via deactivating the COX-2.•COX-2 disturbs hydrolysis of Aβ via suppressing activity of UCH-L1 in lysosomes.•Tyr 385 is critical for the activity of COX-2 in cognitive decline of AD. Nutrient deficiency has been recently suggested to be associated with the deposition of β-amyloid protein (Aβ) during the course of Alzheimer’s disease (AD) development and progression. We thereby aimed to reveal the roles of a deficiency in important mineral nutrient, magnesium ions (Mg2+), in the deposition of Aβ via autophagy mechanisms. Specifically, we report here that Mg2+ functions as a critical enhancer of the formation of the mammalian target of rapamycin complex 1 (mTORC1) by inhibiting the expression and enzymatic activity of cyclooxygenase-2 (COX-2), which is responsible for inducing autophagosome formation, as indicated by the microtubule-associated protein 1 light chain 3 beta (LC3B) puncta. Although autophagosome generation was strongly induced in COX-2 Tg mice, COX-2 overexpression facilitated Aβ deposition by disrupting the proteolytic function of autolysosomes through an ubiquitin carboxy terminal hydrolase L1 (UCH-L1)-depressing mechanism. More interestingly, COX-2 mutation at Tyr 385 restores the activity of UCH-L1, which results in Aβ degradation and improvements in the cognitive decline of APP/PS1 Tg mice.