Mitochondria impact brain function and cognition

Picard, Martin; McEwen, Bruce S.

doi:10.1073/pnas.1321881111

Cited by 197 publications

(137 citation statements)

References 21 publications

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“…Mitochondrial impairment may directly affect energy-hungry synapses, contributing to cognitive deficits 156 . Moreover, increased levels of ROS make trisomic neurons more prone to undergoing apoptosis, potentially making them more likely to degenerate 151 .…”

Section: Mitochondria and Rosmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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Section: Mitochondria and Rosmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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“…Recent research indicates the importance of mitochondrial energy production for excitability and survival of neurons, synaptic signaling and related long-term changes in neuronal structure and function (Mattson et al 2008;Picard and McEwen 2014). Mitochondria produce energy which is among others required to maintain synaptic ion homeostasis and phosphorylation reactions.…”

Section: Behavioral Testingmentioning

confidence: 99%

Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice

et al. 2016

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Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer's disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction in vitro and in short-term in vivo feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD.

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“…For example, moderate GC levels improve performance on spatial memory tasks and adaptive immunity, but high, sustained levels of the steroids can impair performance (4,5). This biphasic pattern, in which acute and chronic stress or corticosteroid exposure have different or even opposed effects, holds for other effects in the nervous system, such as dendritic plasticity and neurogenesis (6,7), and may serve to adapt the nervous system to the energetic demands of environment in many cases, although it may induce pathology in others (8).…”

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confidence: 99%

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Hunter

Seligsohn

Rubin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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130

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Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.nuclear receptors | allostasis | mitochondrial plasticity | brain metabolism | mitochondrial transcription

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Mitochondria impact brain function and cognition

Cited by 197 publications

References 21 publications

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

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