Reproductive Stage and Modulation of Stress‐Induced Tau Phosphorylation in Female Rats

Abstract

Chronic stress is implicated as a risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders. While the specific mechanisms linking stress exposure and AD vulnerability have yet to be fully elucidated, our lab 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. Tau phosphorylation induced by a psychological stressor is reversible and is thought to be dependent on intact signaling through the type 1 corticotropin-releasing factor receptor, but how sex steroids or other modulators may also modulate this effect are unknown. A naturally occurring attenuation of 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 minutes of restraint stress or no stress (control), and were sacrificed at 20 minutes or 24 hours after the episode. Exposure to restraint stress induced a significant decrease in tau-P in the hippocampus of lactating rats sacrificed 20 minutes after stress compared to lactating controls and virgins subjected to stress treatment. Lactating rats sacrificed 24 hours after exposure to restraint stress showed a significant increase in tau-P compared to the restraint-stressed lactating rats sacrificed only 20 minutes after stress exposure, expressing phosphorylation levels similar to control animals. Further, GSK3-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.

Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin

“…We found that exposure to one episode of restraint stress significantly reduced p-Tau in the hippocampus of lactating dams compared to virgin or postweaned rats. This decrease was coupled with reduced detection of GSK3α ( 23 ).…”

“…The fact that diverse results in the AD field have surfaced between males and females at different ages, reproductive stages, and in response to different stimuli points toward a new direction in sex-related AD research ( 23 , 45 , 77 ) (Table 1 ). Thus, detailed attention must be given to the study of aging, different reproductive stages and hormones involved, and the interplay with other risk factors in females ( 21 , 77 ).…”

“…Also, it is extremely important to acknowledge that inflammation plays a critical role in the development of AD, through interactions with risk factors, such as obesity and depression, and with the hormones described above ( 13 , 15 , 41 , 78 ). Further research needs to address inflammation in relation to other risk factors and markers of the disease ( 12 , 15 , 23 ) to elucidate why females appear to be protected from injury and neurodegeneration during lactation and more vulnerable during menopause.…”

“…More importantly, breastfeeding is related to a reduced risk to develop AD, especially when performed for a prolonged period ( 21 ). Likewise, maternal experience results in better performance in hippocampus-dependent learning tasks ( 22 ) and acute stress during lactation induces a decrease in hippocampal p-Tau compared to unstressed controls in rats ( 23 ). The following sections will focus on the role of a specific set of hormones (i.e., estrogen, progesterone, and prolactin) and its consequences for p-Tau.…”

Association between Serum Prolactin Levels and Neurodegenerative Diseases: Systematic Review and Meta-Analysis

“…For example, PRL may regulate neurogenesis, contribute to stress adaptation, and promote neuroprotection; however, PRL also inhibits neurogenesis and promotes depressive-like behaviors [5]. Furthermore, a previous study reported PRL caused negative effects on cognitive function in patients with AD, but another study showed that PRL reduced the risk of AD via inhibition of tau phosphorylation and protected the hippocampus [12, 13]. In a case-control study, PRL responses to fenfluramine were significantly impaired in patients with PD compared to controls and were significantly more blunted in patients with major depression compared to the nondepressed group [14].…”