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.
"Latrepirdine has been shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx, and intracellular catabolic pathways   . 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 . Estrogens promote the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism) . "
[Show abstract][Hide abstract] ABSTRACT: In Alzheimer's disease (AD), molecular changes are observed not only in patients' neurons but also in peripheral cells, such as blood lymphocytes. These include changes in the level of oxidative stress markers, mitochondria impairment, and aberrant cell cycle regulation in AD blood lymphocytes. While the concepts of early causes of AD are currently highly controversial, these findings provide support for the cell cycle hypothesis of AD pathomechanism and emphasize the systemic nature of the disease. Moreover, because of difficulties in studying dynamic processes in the human brain, lymphocytes seem to be useful for readout of AD molecular mechanisms. In addition, lymphocytes as easily accessible human cells have potential diagnostic value. We summarize current perspectives for the development of new therapeutic strategies based on oxidative stress and cell cycle dysregulation in AD, and for diagnostic methodologies involving new markers in AD lymphocytes.
"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. "
[Show abstract][Hide abstract] ABSTRACT: With the aging of the population, the burden of Alzheimer's disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD.
"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. "
[Show abstract][Hide abstract] 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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