Accelerated Ovarian Failure (AOF) is an Effective Transitional Menopausal Model for the Study of Alzheimer’s Disease

Background

Biological females account for 70% of Alzheimer’s disease (AD) cases. It’s hypothesized that the estrogen depletion females experience during menopause is a factor in the pathogenesis of AD¹. The gold standard rodent model of ovariectomy doesn’t allow for the examination of the gradual loss of estrogen that occurs in humans through perimenopause to menopause². Administration of 4‐vinylcyclohexene diepoxide (VCD) has emerged as a rodent model of transitional menopause. The goal of this study was to determine how AD and neuronal markers were impacted by the gradual depletion of estrogen in a VCD model of transitional menopause.

Method

Mature CD1 female mice were injected with VCD (160 mg/kg/d IP for 15 days) to cause gradual ovarian failure over 120 days. A control group was also injected with a vehicle. Sample was collected at four timepoints, two representative of early and late perimenopause (60 and 120 days post injection) while the other two represented early and late menopause (137 and 176 days post injection). At each timepoint, novel object recognition testing (NORT) was performed to assess changes in behavior and memory². At euthanasia, the prefrontal cortex and hippocampus were collected for protein analysis.

Result

The NORT demonstrated that the VCD groups at all timepoints had lowered activate memory recall. The prefrontal cortex western blotting results demonstrated that the VCD mice had lower NeuN content across all timepoints. NeuN is a marker of mature neurons which when lowered can have detrimental consequences on memory. SNAP25, a pre‐synaptic protein involved in neuronal synaptic communication, was also lower in the prefrontal cortex of VCD mice across all timepoints.

Conclusion

The VCD model had impacts on active memory recall which was accompanied by reductions in neuronal and synaptic markers. This indicates that the loss of estrogen through transitional menopause results in early changes in neuronal markers and memory.

1. Iqbal, J. & Zaidi, M. Understanding Estrogen Action during Menopause. Endocrinology 150, 3443‐3445 (2009).

2. Mohammad, A., Finch, M. S., Sweezey‐Munroe, J. & MacPherson, R. E. K. Voluntary wheel running alters markers of amyloid‐beta precursor protein processing in an ovarian hormone depleted model. Front. Endocrinol. 13, 1069404 (2022).