Estrogen Regulation of Mitochondrial Bioenergetics. Implications for Prevention of Alzheimer's Disease

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Advances in pharmacology (San Diego, Calif.) 07/2012; 64:327-71. DOI: 10.1016/B978-0-12-394816-8.00010-6
Source: PubMed


Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.

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    • "Latrepirdine has been shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx, and intracellular catabolic pathways [178] [179] [180]. Estrogens also enhance neural survival and health through the regulation of mitochondrial bioenergetics, maintenance of calcium homeostasis, the promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and A␤ clearance [181]. Estrogens promote the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism) [182]. "
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    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-141977 · 4.15 Impact Factor
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    • "Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines,108,109 maintaining hippocampal function during aging;110 improving cerebral blood flow and glucose metabolism,111 increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function),112,113 reducing the aggregation of amyloid-beta and associated neurotoxicity,114,115 and preventing mitochondrial damage.116 Despite the apparent benefits in animal and cellular models, the impact of estrogen loss (due to natural menopause or surgically induced) and of hormone replacement therapy (HRT), on the risk of AD in women remains controversial. "
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    • "c o m / l o ca t e / n e u a g i n g in the respiratory chain have been reported to increase ROS production. However, it is unclear whether mitochondria are the sole contributor to the ROS damage seen in AD, because alternative sources of ROS have also been identified (Abramov et al., 2004; Cutler et al., 2004; Yao and Brinton, 2012). We examined the effect of mtDNA damage on Ab accumulation and plaque formation to determine how a mild mitochondrial dysfunction affects the pathophysiological changes that occur in a mouse model of AD. "
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    ABSTRACT: Mitochondrial DNA (mtDNA) damage and the generation of reactive oxygen species have been associated with and implicated in the development and progression of Alzheimer's disease. To study how mtDNA damage affects reactive oxygen species and amyloid beta (Aβ) pathology in vivo, we generated an Alzheimer's disease mouse model expressing an inducible mitochondrial-targeted endonuclease (Mito-PstI) in the central nervous system. Mito-PstI cleaves mtDNA causing mostly an mtDNA depletion, which leads to a partial oxidative phosphorylation defect when expressed during a short period in adulthood. We found that a mild mitochondrial dysfunction in adult neurons did not exacerbate Aβ accumulation and decreased plaque pathology. Mito-PstI expression altered the cleavage pathway of amyloid precursor protein without increasing oxidative stress in the brain. These data suggest that mtDNA damage is not a primary cause of Aβ accumulation.
    Neurobiology of aging 05/2013; 34(10). DOI:10.1016/j.neurobiolaging.2013.04.014 · 5.01 Impact Factor
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