Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid

Area of Science:

• Neuroscience
• Endocrinology
• Mitochondrial Biology

Background:

• Reproductive senescence correlates with mitochondrial deficits, mirroring those in female triple-transgenic Alzheimer's disease (3xTgAD) mice.
• Ovarian hormone status significantly influences brain health and mitochondrial function.

Purpose of the Study:

• To investigate the effects of ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in female non-transgenic (nonTg) and 3xTgAD mouse brains.
• To determine if E2 can mitigate hormone loss-induced mitochondrial dysfunction and Alzheimer's-like pathology.

Main Methods:

• Ovariectomy (OVX) was performed on nonTg and 3xTgAD female mice to deplete ovarian hormones.
• Mice were treated with E2 post-OVX.
• Brain bioenergetics, mitochondrial function, oxidative stress, and expression of mitochondrial β-amyloid and ABAD were assessed.
• In vitro studies examined E2's effect on neuronal and glial mitochondrial respiration.

Main Results:

• OVX in nonTg mice decreased brain bioenergetics, induced mitochondrial dysfunction, and increased oxidative stress.
• OVX exacerbated mitochondrial dysfunction and increased mitochondrial β-amyloid and ABAD expression in 3xTgAD mice.
• E2 treatment in OVX mice prevented mitochondrial deficits, sustained bioenergetics, reduced oxidative stress, and inhibited mitochondrial β-amyloid and ABAD accumulation.
• In vitro, E2 enhanced mitochondrial respiration in both neurons and glia.

Conclusions:

• Ovarian hormone loss induces a mitochondrial phenotype comparable to a female Alzheimer's disease model.
• E2 replacement therapy effectively prevents hormone loss-induced mitochondrial dysfunction and associated pathology.
• These findings suggest a mechanism linking premature menopause to increased Alzheimer's risk and highlight E2 as a potential preventive therapeutic strategy.