The ABCD's of 5'-adenosine monophosphate-activated protein kinase and adrenoleukodystrophy.

This Editorial highlights a study by Singh and coworkers in the current issue of Journal of Neurochemistry, in which the authors present additional evidence that AMPKα1 is reduced in X-linked adrenoleukodystrophy (X-ALD). They make a case for increasing AMPKα1 activity for therapeutic purposes in this disease, and indicate how this goal may be achieved. Read the highlighted article 'Metformin-induced mitochondrial function and ABCD2 up regulation in X-linked adrenoleukodystrophy involves AMP activated protein kinase' on page 86.

Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure.

We tested how the addition of oxaloacetate (OAA) to SH-SY5Y cells affected bioenergetic fluxes and infrastructure, and compared the effects of OAA to malate, pyruvate, and glucose deprivation. OAA displayed pro-glycolysis and pro-respiration effects. OAA pro-glycolysis effects were not a consequence of decarboxylation to pyruvate because unlike OAA, pyruvate lowered the glycolysis flux.

Open-source, Rapid Reporting of Dementia Evaluations.

The National Institutes of Health Alzheimer's Disease Center consortium requires member institutions to build and maintain a longitudinally characterized cohort with a uniform standard data set. Increasingly, centers are employing electronic data capture to acquire data at annual evaluations. In this paper, the University of Kansas Alzheimer's Disease Center reports on an open-source system of electronic data collection and reporting to improve efficiency.

Modeling Percentile Rank of Cardiorespiratory Fitness Across the Lifespan.

Purpose: The purpose of this investigation was to create an equation for continuous percentile rank of maximal oxygen consumption (VO max) from ages 20 to 99.

Methods: We used a two-staged modeling approach with existing normative data from the American College of Sports Medicine for VO max. First, we estimated intercept and slope parameters for each decade of life as a logistic function.

GRK5 deficiency leads to susceptibility to intermittent hypoxia-induced cognitive impairment.

Obstructive sleep apnea (OSA) leads to cognitive impairment in about 25% patients, though it remains elusive what makes one more susceptible than the other to be cognitively impaired. G protein-coupled receptor kinase-5 (GRK5) deficiency is recently found to render subjects more susceptible to cognitive impairment triggered by over-expression of Swedish mutant ß-amyloid precursor protein. This study is to determine whether GRK5 deficiency also renders subjects more susceptible to the OSA-triggered cognitive impairment.

Lactate's effect on human neuroblastoma cell bioenergetic fluxes.

Lactate, once considered a metabolic dead-end, has been recently proposed to support neuron bioenergetics. To better understand how lactate specifically influences cell energy metabolism, we studied the effects of lactate supplementation on SH-SY5Y human neuroblastoma cell bioenergetic fluxes. Lactate supplementation increased cell respiration, there was no change in respiratory coupling efficiency, and lactate itself appeared to directly support the respiratory flux increase.

Dose-Response of Aerobic Exercise on Cognition: A Community-Based, Pilot Randomized Controlled Trial.

Unlabelled: Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition.

Mitochondrial lysates induce inflammation and Alzheimer's disease-relevant changes in microglial and neuronal cells.

Neuroinflammation occurs in Alzheimer's disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-β protein promotes inflammation, our understanding of AD neuroinflammation nevertheless remains incomplete. In this study we hypothesized damage-associated molecular pattern (DAMP) molecules arising from mitochondria, intracellular organelles that resemble bacteria, could contribute to AD neuroinflammation.

Evaluating Variables as Unbiased Proxies for Other Measures: Assessing the Step Test Exercise Prescription as a Proxy for the Maximal, High-intensity Peak Oxygen Consumption in Older Adults.

To assess validity of a low-intensity measure of fitness () in a population of older adults as a proxy measure for the original, high-intensity measure (), we used ordinary least square regression with the new, potential proxy measure () as the sole explanatory variable for . A perfect proxy measure would be unbiased (i.e.

Cytoplasmic hybrid (cybrid) cell lines as a practical model for mitochondriopathies.

Cytoplasmic hybrid (cybrid) cell lines can incorporate human subject mitochondria and perpetuate its mitochondrial DNA (mtDNA)-encoded components. Since the nuclear background of different cybrid lines can be kept constant, this technique allows investigators to study the influence of mtDNA on cell function. Prior use of cybrids has elucidated the contribution of mtDNA to a variety of biochemical parameters, including electron transport chain activities, bioenergetic fluxes, and free radical production.

Bioenergetic dysfunction and inflammation in Alzheimer's disease: a possible connection.

Inflammation is observed in Alzheimer's disease (AD) subject brains. Inflammation-relevant genes are increasingly implicated in AD genetic studies, and inflammatory cytokines to some extent even function as peripheral biomarkers. What underlies AD inflammation is unclear, but no "foreign" agent has been implicated.

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis.

Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation.

In aged mice, we assessed how intensive exercise affects brain bioenergetics, inflammation, and neurogenesis-relevant parameters. After 8 weeks of a supra-lactate threshold treadmill exercise intervention, 21-month-old C57BL/6 mice showed increased brain peroxisome proliferator-activated receptor gamma coactivator-1α protein, mammalian target of rapamycin and phospho-mammalian target of rapamycin protein, citrate synthase messenger RNA, and mitochondrial DNA copy number. Hippocampal vascular endothelial growth factor A (VEGF-A) gene expression trended higher, and a positive correlation between VEGF-A and PRC messenger RNA levels was observed.

LRRK2, a puzzling protein: insights into Parkinson's disease pathogenesis.

Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson's disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity.

Cardiopulmonary exercise testing is well tolerated in people with Alzheimer-related cognitive impairment.

Objective: To retrospectively assess whether cardiopulmonary exercise testing would be well tolerated in individuals with Alzheimer disease (AD) compared with a nondemented peer group.

Design: We retrospectively reviewed 575 cardiopulmonary exercise tests (CPETs) in individuals with and without cognitive impairment caused by AD.

Setting: University medical center.

Altering O-linked β-N-acetylglucosamine cycling disrupts mitochondrial function.

Mitochondrial impairment is commonly found in many diseases such as diabetes, cancer, and Alzheimer disease. We demonstrate that the enzymes responsible for the addition or removal of the O-GlcNAc modification, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, are critical regulators of mitochondrial function. Using a SILAC (stable isotope labeling of amino acids in cell culture)-based proteomics screen, we quantified the changes in mitochondrial protein expression in OGT- and OGA-overexpressing cells.

Reducing post-lumbar puncture headaches with small bore atraumatic needles.

Lumbar puncture for testing of Alzheimer's disease pathophysiology for diagnostic confirmation is likely to become more common in the coming years. Minimizing adverse effects from this testing will be essential for clinical practice. Small bore, atraumatic needles reduce the occurrence of post-lumbar puncture headache (PLPH).

Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.

There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer's Disease-related brain imaging and cognitive markers of disease.

The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives.

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it.

Lactate administration reproduces specific brain and liver exercise-related changes.

The effects of exercise are not limited to muscle, and its ability to mitigate some chronic diseases is under study. A more complete understanding of how exercise impacts non-muscle tissues might facilitate design of clinical trials and exercise mimetics. Here, we focused on lactate's ability to mediate changes in liver and brain bioenergetic-associated parameters.

Should we disclose amyloid imaging results to cognitively normal individuals?

Demonstration of brain accumulation of fibrillar amyloid beta protein via positron emission tomography (PET) with amyloid specific ligands may support the diagnosis of Alzheimer's disease (AD). There is increasing recognition of the potential use of amyloid imaging to detect the pathology of AD in individuals with no ostensible cognitive impairment. Research use of amyloid PET in cognitively normal patients will be key to pursuit of therapies able to delay cognitive impairment and dementia due to AD.