Alzheimer's disease (AD) is the most common form of dementia, accounting for approximately 60–80% of all dementia cases (Alzheimer’s Association, 2011; Blennow et al., 2006). Symptoms of the disease range from mild memory difficulties to progressive cognitive impairment and inability to perform daily activities. The main histological brain features of AD include loss of neurons in the cerebral cortex and hippocampus, and the presence of plaques formed by amyloid β (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (Albert et al., 2011; DeTure and Dickson, 2019). Precursor and mature Aβ can translocate to mitochondria and interfere with mitochondrial function (Calvo-Rodriguez et al., 2020; Chen and Yan, 2010; Muirhead et al., 2010). Hyperphosphorylated tau also affects mitochondrial dynamics (DuBoff et al., 2012; Götz et al., 2013; Trease et al., 2022).

Mitochondrial adenosine 5′-triphosphate (ATP) production is necessary for normal cellular function, especially for cells such as neurons that require large amounts of energy (Mattson et al., 2008). Therefore, the balance between mitochondrial biogenesis and destruction through mitophagy is critical for normal cellular function. Mitochondrial biogenesis is coordinated by nuclear transcription factors that regulate the expression of genes encoding mitochondrial proteins. These transcription factors include nuclear respiratory factor (NRF) 1 and 2 as well as mitochondrial transcription factor A (mtTFA); their expression is in turn regulated by peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) (Wu et al., 1999). Impaired mitochondrial biogenesis may contribute to the pathogenesis of neurodegenerative diseases. For example, AD patients and AD cellular models show downregulation of PGC-1α, NRF1, NRF2, and mtTFA, implying decreased mitochondrial biogenesis (Sheng et al., 2012). Upregulation of PGC-1α increases mitochondrial biogenesis and can mitigate cognitive impairment in the mouse model of AD (Yin et al., 2022; Zhu et al., 2012). Therefore, enhancing mitochondrial biogenesis may be an effective approach for treatment of AD.

Analogously to the deficiency in mitochondrial biogenesis, deficiency in mitochondrial destruction through mitophagy has been associated with AD and other neurodegenerative diseases (Fang et al., 2019; Pickrell and Youle, 2015; Reddy and Oliver, 2019). There are three main types of mitophagy: one depends on Pink1/Parkin signaling (Koyano et al., 2014; Okatsu et al., 2012); another depends on the outer mitochondrial membrane receptors FUNDC1, NIX, BCL2L13, and FKBP8 (Bhujabal et al., 2017; Liu et al., 2012; Murakawa et al., 2015; Novak et al., 2010); and the third depends on translocation of cardiolipin from the inner to outer mitochondrial membrane, in a process involving LC3 (Kagan et al., 2016; Li et al., 2015). Loss of Parkin, NIX, or FUNDC1 results in the accumulation of functionally impaired, swollen mitochondria (Li et al., 2019; McWilliams and Muqit, 2017; Sandoval et al., 2008). Aβ and tau inhibit mitophagy, while mitophagy appears to prevent accumulation of Aβ and tau phosphorylation (Fang et al., 2019). These observations suggest that upregulating mitophagy may be used for treatment of AD.

Approximately two-thirds of AD patients are postmenopausal women, suggesting that the decrease in estrogen levels after menopause strongly increases the risk of AD (Paganini-Hill and Henderson, 1994; Yue et al., 2005). Indeed, we have shown that estrogen deficiency in mice significantly reduces mitochondrial biogenesis and mitophagy in hippocampus (Hou et al., 2022; Zhao et al., 2021). Estrogen has been found to regulate mitochondrial function possibly through ERα and ERβ, promote mtDNA transcription by stimulating NRF1 transcription and binding to mtDNA (Chen et al., 2009; Klinge, 2008) and enhance mitochondrial function through transcription of nuclear encoded electron transfer chain proteins, such as mitochondrial ATP synthase subunit and COVII (Chen et al., 2008). Whether mitochondrial ERα and ERβ play a direct role in mitochondrial DNA gene transcription and mitochondrial function appears to depend on the cell type (Scarpulla, 2012). However, the protective effects of estrogen on brain mitochondria remain to be fully elucidated.

Estrogen-replacement therapy can mitigate AD symptoms in postmenopausal women, but the hormone has multiple effects, leading to an increase in the risk of cancer and thromboembolism (Beral, 2003; Henderson and Lobo, 2012; Stahlberg et al., 2004). Therapies targeting the estrogen receptor (ER), particularly its β isoform, may avoid such side effects. Targeting ERβ should avoid gonadal side effects when the α isoform is altered (Zhao and Brinton, 2005). ERβ is expressed primarily in brain regions related to learning and memory, such as the cerebral cortex, hippocampus, and basal forebrain (Foster, 2012; Mitterling et al., 2010), and levels of ERβ in the brain decrease with age (Wilson et al., 2002; Yamaguchi and Yuri, 2012). Therefore, this ER isoform may be the most suitable target for preventing neurodegenerative disease.

We hypothesized that ERβ may be involved in attenuating AD symptoms in postmenopausal women by regulating NRF1/PGC-1α signaling to balance mitochondrial biogenesis and mitophagy. More specifically, upregulating or activating the receptor may be a therapeutic approach to AD. The hypothesis was tested using mouse models of postmenopausal AD and ERβ knockdown, as well as primary hippocampal neurons exposed to Aβ.