The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.
Novel therapeutic approach for preeclampsia: targeting autophagy pathways: Autophagy, a process in cells that helps maintain organ growth and balance, is important for the immune system and stress response. However, when autophagy doesn’t work properly, it can lead to diseases, including preeclampsia, a serious pregnancy issue. Dr. Surendra Sharma and his team at the Women and Infants Hospital of Rhode Island discovered that trehalose, a natural sugar, can fix autophagy and restore the ability of the cell’s waste disposal system. They tested this on human cells and a mouse model of preeclampsia. The results showed that trehalose and a similar sugar, lactotrehalose, effectively fixed autophagy, stopped harmful protein buildup, and reduced the production of harmful factors associated with preeclampsia. This suggests that sugars like trehalose could be potential treatments for preeclampsia. “This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.”