Fig. 5

Possible interaction between various transcription factors and transcriptional coactivators contributing to the observed increase in adenosine triphosphate (ATP) concentrations in response to curcumin supplementation in APOE3 and APOE4 mice. Peroxisome proliferator-activated receptor (PPAR) γ coactivator (PGC)-1α is a transcriptional coactivator that functions as a key regulator for energy homeostasis and mitochondrial biogenesis. PGC1α was previously shown to interact with the guanine–adenine repeat binding protein alpha subunit (GABPa) to induce increased mitochondrial biogenesis and mitochondrial respiratory capacity. This mechanism could explain the increased mitochondrial respiratory capacity after curcumin supplementation in APOE3 mice since the activation of mitochondrial transcription factor A (TFAM) through GABPa possibly led to the increased protein concentrations of mitochondrial respiratory complexes and increased ATP concentrations. Curcumin effects in APOE3 mice might also be mediated by PPARγ. Although PPARγ has not been associated with the regulation of mitochondrial respiratory complexes, PPARγ may indirectly enhance mitochondrial biogenesis by activating the PPARγ responsive element found in the gene promoter region of PGC1α, thereby increasing the transcription of PGC1α. In APOE4 mice, curcumin only induced a slight increase in PGC1α but did not seem to induce downstream PPARγ or GABPa. TFAM was even decreased in APOE4 mice. An alternative pathway might be responsible for the increased ATP concentrations in APOE4 mice