Estrogen receptor β exerts neuroprotective effects by fine-tuning mitochondrial homeostasis through NRF1/PGC-1α

Background: Estrogen deficiency causes mitochondrial defects that precede pathological changes related to Alzheimer's disease (AD) in the mouse model of postmenopause. The aim of this study was to investigate in such a mouse model whether and how estrogen receptor beta (ER beta) was involved in prevention of mitochondrial damage and protection of neurons in the hippocampus.Methods: A mouse model of postmenopausal AD was created by ovariectomizing female 3xTg-AD mice, some of which were subcutaneously injected for six weeks with the non-steroidal ER beta agonist diarylpropionitrile. ER beta expression in female C57BL/6J mice was knocked down using shRNA interference. The different groups of animals were compared in terms of cognitive function using the Y-maze test, new object recognition test, and Morris water maze test, expression of numerous proteins related to mitochondrial biogenesis, mitophagy, apoptosis, and mitochondrial membrane potential, as well as deposition of amyloid beta and neurofibrillary tangles. To complement these in vivo studies, we probed the effects of diarylpropionitrile on ER beta expression, apoptosis, and mitochondrial homeostasis in primary rat hippocampal neurons treated with amyloid beta.Results: ER beta knockdown in C57BL/6J mice produced cognitive impairment, reduced mitochondrial biogenesis by downregulating PGC-1 alpha, NRF1, mtTFA, and TOM20, and decreased mitophagy by downregulating Pink1, Parkin, and LC3B while upregulating PARIS and p62. ER beta knockdown promoted neuronal apoptosis by upregulating Cleaved-Caspase 9, Cleaved-Caspase 3, and Bax, while downregulating Bcl2 in hippocampus. Diarylpropionitrile mitigated cognitive decline in ovariectomized 3xTg-AD mice, which was associated with downregulation of BACE1, reduction of A beta deposition, neurofibrillary tangles, and tau hyperphosphorylation, and upregulation of ER beta, increases in mitochondrial biogenesis and mitophagy, and decreases in apoptosis. The effects of diary-lpropionitrile in mice were recapitulated in A beta-injured primary rat hippocampal neurons.Conclusions: ER beta activation can support learning and memory and alleviate AD symptoms in the postmenopausal AD model, which may involve regulation of neuronal mitochondrial biogenesis and mitophagy via NRF1/PGC-1 alpha. This study supports further research on ER beta as a therapeutic target for postmenopausal women with AD.

Automated summary

This study demonstrates that the activation of ERβ can support learning and memory, and alleviate symptoms of postmenopausal AD model by regulating neuronal mitochondrial biogenesis and mitophagy.