Late-onset Alzheimer's disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly-C tract heteroplasmy (original) (raw)

Body-wide changes in bioenergetics, i.e., energy metabolism, occur in normal aging and disturbed bioenergetics may be an important contributing mechanism underlying late-onset Alzheimer's disease (LOAD). We investigated the bioenergetic profiles of fibroblasts from LOAD patients and healthy controls, as a function of age and disease. LOAD cells exhibited an impaired mitochondrial metabolic potential and an abnormal redox potential, associated with reduced nicotinamide adenine dinucleotide metabolism and altered citric acid cycle activity, but not with disease-specific changes in mitochondrial mass, production of reactive oxygen species, transmembrane instability, or DNA deletions. LOAD fibroblasts demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to IGF-1. The increase of glycolysis and the abnormal mitochondrial metabolic potential in LOAD appeared to be inherent, as they were disease-and not age-specific. Our findings support the hypothesis that impairment in multiple interacting components of bioenergetic metabolism may be a key mechanism contributing to the risk and pathophysiology of LOAD. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by slow progressive deterioration and death of neurons. A number of interacting factors determine the risk of AD and among the better-studied pathophysiologic pathways, the "amyloid cascade hypothesis" proposes that AD is precipitated by an accumulation of Aβ-containing plaques and tangles of hyperphosphorylated tau (p-tau) 1-3. This hypothesis is best supported for familial/early-onset forms of AD (EOAD), while less so for the more common sporadic/ late-onset forms (LOAD) 4,5. In LOAD, accumulation of toxic Aβ and p-tau may not be the initial cause of neural degeneration and may instead be consequences of other causative factors 5,6. Changes in bioenergetics, i.e., energy metabolism, are part of the normal aging process and disturbed bioenergetics may be a contributing mechanism underlying LOAD 7-10. These anomalies are body-wide, but affect the brain most substantially because of its exceptionally high-energy requirements. Thus, changes of bioenergetics and metabolism could be at the core of determining the survival capacities of brain cells with age and under stress, with these processes influenced, in turn, by genetic predisposition, epigenetics, environment, and lifestyle. Bioenergetics is the metabolism of various fuel molecules to produce and utilize energy through glycolysis, mitochondrial respiration, that is, oxidative phosphorylation (OxPhos), or the pentose phosphate pathway (PPP). Healthy eukaryotic cells produce ATP about 12% through glycolysis and 88% through OxPhos, on average. In the 1920s, German physician-chemist Otto Warburg discovered that mammalian cancer cells can switch from OxPhos to glycolysis when exposed to low oxygen, called the "Warburg effect" 11. Unlike proliferating cells, post-mitotic neurons have very little ability to use glycolysis, as they lack key enzymes in the glycolytic pathway, e.g., there is evidence that neurons have very low levels of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key enzyme in the glycolytic pathway, due to heightened degradation through the ubiquitin proteasome system (UPS) 12,13. Thus, neurons don't ordinarily make adaptive and compensatory shifts to glycolysis, including under stress conditions. Instead, they have a high demand for other oxidative substrates and, in particular, lactate, which is largely provided by proliferating astrocytes through their high glycolytic capacity. While