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

Chronic stress is implicated as a risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders. Although the specific mechanisms linking stress exposure and AD vulnerability have yet to be fully determined, our laboratory and others have shown that acute and repeated restraint stress in rodents leads to an increase in hippocampal tau phosphorylation (tau-P) and tau insolubility, a critical component of tau pathology in AD. Although tau phosphorylation induced by acute psychological stress is dependent on intact signaling through the type 1 corticotropin-releasing factor receptor, how sex steroids or other modulators contribute to this effect is unknown. A naturally occurring attenuation of the stress response is observed in female rats at the end of pregnancy and throughout lactation. To test the hypothesis that decreased sensitivity to stress during lactation modulates stress-induced tau-P, cohorts of virgin, lactating and weaned female rats were subjected to 30 min of restraint stress or no stress (control) and were killed 20 min or 24 h after the episode. Exposure to restraint stress induced a significant decrease in tau-P in the hippocampus of lactating rats killed 20 min after stress compared to lactating controls and virgins subjected to stress treatment. Lactating rats killed 24 hr after restraint stress exposure showed significant elevation in tau-P compared to lactating cohorts killed 20 min after stress. Levels of tau-P in these latter cohorts did not differ signficantly from control animals. Furthermore, glycogen synthase kinase (GSK)3-α levels were significantly decreased in stressed lactating animals at both timepoints. This suggests a steep, yet transient stress-induced dephosphorylation of tau, influenced by GSK3, in the hippocampus of lactating rats.