UC San Diego

Chronic stress is a consistently implicated risk factor for neurodegenerative diseases like Alzheimer's disease (AD). Hyperphosphorylated tau tangle are a hallmark of AD pathology, and while the specific mechanisms that link stress and AD vulnerability have not been fully elucidated, our lab has shown that acute and repeated restraint stress leads to an increase in hippocampal tau phosphorylation (tau-P) in rodents, a process regulated by the two known corticotropin-releasing factor receptors. A naturally occurring attenuation of stress response is present in female rats during the last part of pregnancy and throughout lactation. Further, the hippocampus of a lactating female is more resistant to the effects of a neurotoxin and the ratio of hippocampal Tau-P/Tau is modified by pregnancy and lactation. To test the hypothesis that the decreased sensitivity to stress during lactation modulates stress-induced tau-P, cohorts of virgin, lactating, or weaned female rats were subjected to 30 minutes of restraint stress or no stress (control) and sacrificed 20 minutes or 24 hours after the episode. Western blot was used to analyze differences at well characterized AD-relevant tau-P epitopes and relevant kinases. Lactating rats sacrificed 20 minutes after the stress episode exhibited a significant tau-P decrease compared to lactating controls as well as virgins subjected to the same stress treatment. Stressed lactating rats sacrificed 24 hours after the episode showed a significant increase in tau-P compared to the lactating stressed rats sacrificed at 20 minutes, returning to control levels. This suggests a steep, yet transient stress-induced dephosphorylation of tau in lactating rats