FEMALE-SPECIFIC THERMOREGULATORY IMPAIRMENTS IN 3XTG-AD MICE: INVOLVEMENT OF NK3 RECEPTOR-DEPENDENT PATHWAYS

Alzheimer’s disease (AD) disproportionately affects women after menopause and is associated not only with cognitive decline but also with systemic disturbances, including impaired thermoregulation. Understanding these alterations may reveal novel therapeutic targets.
Aims: To characterize thermoregulatory alterations in female 3xTg-AD mice and to examine the influence of ovarian hormone loss and NK3R-mediated pathways.
Methods: Core body temperature (cBT) was continuously monitored using implantable telemetry in female 3xTg-AD and wild-type (WT) mice during cold and warm exposure tests and following acute administration of senktide, a selective NK3R agonist mimicking hot flushes. Ovariectomy (OVX) was used to accelerate disease progression and model hormonal loss. Brown adipose tissue gene expression (Ucp1, Dio2, Adrb3) was assessed by quantitative PCR.
Results: Cold exposure induced comparable cBT responses across genotypes and hormonal states. During warm exposure, intact 3xTg-AD females exhibited an exaggerated compensatory thermoregulatory response compared to WT controls; this genotype difference was abolished following OVX. Senktide treatment induced a significant reduction in cBT in WT females, consistent with NK3R-mediated vasodilatory thermoregulation, whereas this response was significantly attenuated in 3xTg-AD mice. OVX significantly altered senktide-induced temperature dynamics and further accentuated genotype-dependent differences. No significant differences were detected in Ucp1 or Dio2 expression; however, Adrb3 showed a marginal increase, suggesting subtle alterations in sympathetic regulation of peripheral thermogenesis.
Conclusion: These findings demonstrate female-specific and hormone-dependent disruptions of thermoregulation in the 3xTg-AD model and identify impaired NK3R-mediated pathways as a potential contributor to systemic physiological dysregulation in Alzheimer’s disease.