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Background  To validate our speculation that curcumin may ameliorate Alzheimer’s disease (AD) pathogenesis by regulating PI(3,5)P2 and transient receptor potential mucolipin-1 (TRPML1) expression levels.    Methods  We developed an animal model presenting AD by APP/PS1 transgenes. The mouse clonal hippocampal neuronal cell line HT-22 was treated with amyloid-β1-42 (Aβ1-42). Curcumin was administrated both  in vivo  and  in vitro . MTS assay was used to detect cell viability, and the lysosomal [Ca 2+ ] ion concentration was detected. The number of autophagosomes was detected by the transmission electron microscopic examination. Illumina RNA-seq was used to analyze the different expression patterns between Aβ1-42-treated cells without and with curcumin treatment. The protein level was analyzed by the Western blotting analysis. PI(3,5)P2 or TRPML1 was knocked down in HT-22 cells or in APP/PS1 transgenic mice. Morris water maze and recognition task were performed to trace the cognitive ability.    Results  Curcumin increased cell viability, decreased the number of autophagosomes, and increased lysosomal Ca 2+  levels in Aβ1-42-treated HT-22 cells. Sequencing analysis identified TRPLML1 as the most significantly upregulated gene after curcumin treatment. Western blotting results also showed that TRPML1 was upregulated and mTOR/S6K signaling pathway was activated and markers of the autophagy–lysosomal system were downregulated after curcumin use in Aβ1-42-treated HT-22 cells. Knockdown of PI (3,5)P2 or TRPML1 increased the protein levels of markers of the autophagy–lysosomal system after curcumin use in Aβ1-42-treated HT-22 cells, inhibited mTOR/S6K signaling pathway, increased the protein levels of markers of the autophagy–lysosomal system after curcumin use in APP/PS1 mice. Besides, knockdown of PI(3,5)P2 or TRPML1 reversed the protective role of curcumin on memory and recognition impairments in mice with APP/PS1 transgenes.    Conclusion  To some extent, it suggested that the effects of curcumin on AD pathogenesis were, at least partially, associated with PI(3,5)P2 and TRPML1 expression levels.

Curcumin Exerts Effects on the Pathophysiology of Alzheimer’s Disease by Regulating PI(3,5)P2 and Transient Receptor Potential Mucolipin-1 Expression