# Estetrol Enhances Mitochondrial Bioenergetics and Neurite Outgrowth in Cellular Models of Alzheimer’s Disease

## TL;DR

Estetrol improves mitochondrial function and nerve cell growth in Alzheimer's models better than traditional estrogen, offering a safer treatment option.

## Contribution

Estetrol shows superior mitochondrial and neuronal benefits in Alzheimer's models via multi-receptor activation and gene modulation.

## Key findings

- E4 enhances mitochondrial energy production and membrane potential in Alzheimer's cell models.
- E4 promotes neurite outgrowth and outperforms E2 in tauopathy conditions.
- E4 modulates mitochondrial genes, upregulating SLC25A23 and downregulating NDUFA1.

## Abstract

What are the main findings?
Estetrol (E4) boosts mitochondrial energy production and neurite outgrowth in Alzheimer’s disease cell models, showing superior efficacy to 17β-estradiol (E2) in stabilizing metabolic function under tau-pathology conditions.E4 exerts its neuroprotective effects by activating estrogen receptors (ERα, ERβ, and GPER1) and specifically upregulating the mitochondrial phosphate carrier gene, SLC25A23.

Estetrol (E4) boosts mitochondrial energy production and neurite outgrowth in Alzheimer’s disease cell models, showing superior efficacy to 17β-estradiol (E2) in stabilizing metabolic function under tau-pathology conditions.

E4 exerts its neuroprotective effects by activating estrogen receptors (ERα, ERβ, and GPER1) and specifically upregulating the mitochondrial phosphate carrier gene, SLC25A23.

What are the implications of the main findings?
E4 may offer a safer therapeutic alternative to E2 for preserving neuronal function in Alzheimer’s disease, potentially reducing the thrombotic and oncologic risks associated with conventional estrogen therapy.The discovery that E4 directly modulates mitochondrial gene expression provides a novel mechanistic validation for its clinical development as a treatment for metabolic deficits in neurodegeneration.

E4 may offer a safer therapeutic alternative to E2 for preserving neuronal function in Alzheimer’s disease, potentially reducing the thrombotic and oncologic risks associated with conventional estrogen therapy.

The discovery that E4 directly modulates mitochondrial gene expression provides a novel mechanistic validation for its clinical development as a treatment for metabolic deficits in neurodegeneration.

Mitochondrial dysfunction is an early driver of Alzheimer’s disease (AD), and the decline in sex hormones, including 17β-estradiol (E2), at menopause has been linked to AD risk in women. While E2 exerts potent neuroprotective and mitochondrial-regulatory effects, its clinical utility in estrogen replacement therapy (ERT) may be limited by thrombotic and oncologic risks. Estetrol (E4), a fetal estrogen with a selective safety profile, may represent a promising alternative. This study evaluated the impact of E4 on mitochondrial bioenergetics and neuronal morphology in human SH-SY5Y neuroblastoma cells, including models of AD-related amyloidopathy (amyloid precursor protein overexpression) and tauopathy (P301Ltau mutation overexpression). E4 significantly enhanced ATP levels, mitochondrial membrane potential, and oxidative respiration in all cell models, notably outperforming E2 in P301L cells. E4 also promoted significant neurite outgrowth, alleviating deficits observed in AD models. In addition, we demonstrated that the bioenergetic effects of E4 were mediated by the estrogen receptors ERα, ERβ, and GPER1. Furthermore, E4 modulated the expression of key mitochondrial genes, specifically upregulating the phosphate carrier SLC25A23 while downregulating the complex I subunit NDUFA1. In conclusion, E4 improves mitochondrial health and supports neuronal integrity via a multi-receptor mechanism, highlighting its potential as a safe neuroprotective therapy for AD.