White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease

Klosinski, Lauren; Yao, Jia; Yin, Fei; Fonteh, Alfred N.; Harrington, Michael G.; Christensen, Trace; Trushina, Eugenia; Brinton, Roberta Dı́az

doi:10.1016/j.ebiom.2015.11.002

Cited by 142 publications

(141 citation statements)

References 118 publications

(177 reference statements)

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“…Moreover, it is proved to be neuroprotective in HD and stroke models AD and HD [114] Melatonin Improves the ultrastructure of mitochondria in the neurons of the CA1 region and prevents the decrease in the mitochondria-occupied portion of the neuronal volume in AD AD [115] Mori Fructus (ME) Decreases mitochondria depolarization, Cyt c release from mitochondria and caspase-3 activation induced by Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) toxicity in the mouse hippocampus AD [116] Erythropoietin (EPO) Alleviates the Aβ-induced mitochondrial dysfunction and apoptosis in brain AD [117] Linagliptin…”

Section: Methazolamide (Mtz)mentioning

confidence: 99%

“…Recently, white matter degeneration in aging brain has found to be associated with mitochondrial dysfunction, underlying the greatest risk of AD. Moreover, it also causes reduced mitochondrial respiration and increased mitochondrial H 2 O 2 productions [35]. In the same way, accumulation of discriminant metabolites such as acylcarnitines has also reported to involve in impaired mitochondrial function [36].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

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Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

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Section: Methazolamide (Mtz)mentioning

confidence: 99%

Section: Alzheimer's Diseasementioning

confidence: 99%

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…We propose that one fundamental difference between the ApoE ɛ4 brain and Apoe 2 and 3 brains is in reliance of the ApoE ɛ4 brain on ketone bodies as a bioenergetic fuel. Reliance of the ApoE ɛ4 brain on ketone bodies as a bioenergetic fuel puts that brain at risk for utilization of its own white matter as fuel (29). In the female brain, estrogen activates the system biology of glucose metabolism while simultaneously suppressing the ketogenic system in brain thereby promoting brain reliance on glucose as its primary fuel to generate ATP (17, 28, 131–138).…”

Section: Sex Differences In Apoe Genotype and Risk Of Alzheimer’smentioning

confidence: 99%

“…Further, aging is typified by a coordinated series of sequential steps involving specific pathways at each phase in the aging process (17, 28). Systems either driving brain aging are contributors to risk of AD and include glucose hypometabolism and mitochondria dysfunction, innate immune and inflammatory reactions, beta amyloid processing, dysregulation of cholesterol homeostasis, white matter degeneration and decline in regenerative capacity (16, 17, 19, 21, 22, 24–26, 29, 30)…”

Section: Introductionmentioning

confidence: 99%

Age, APOE and sex: Triad of risk of Alzheimer’s disease

Riedel

Thompson

Brinton

2016

The Journal of Steroid Biochemistry and Molecular Biology

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485

400

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Age, apolipoprotein E ɛ4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer’s disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ɛ4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ɛ4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ɛ4 allele. Paradoxically, men homozygous for APOE-ɛ4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer’s disease, age, APOE-ɛ4 genotype and female sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the unique risk of the APOE4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer’s disease.

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“…Deficient glucose metabolism necessitates alternative sources to satisfy energetic demands. One potential candidate is lipid metabolism, in particular ketone bodies [12, 13]. …”

Section: Introductionmentioning

confidence: 99%

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

Chen

Tran

Hwang

et al. 2016

JHD

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Background Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission. Objective Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined. Methods Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone β-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD). Results Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet. Conclusions Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.

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White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease

Cited by 142 publications

References 118 publications

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Age, APOE and sex: Triad of risk of Alzheimer’s disease

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

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