Abstract
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.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by slow progressive deterioration and death of neurons
While the underlying causes of bioenergetic dysfunctions in aging and degenerating cells may be in part due to an increase in mitochondrial damage and dysfunction, deficiencies in glucose processing and glycolysis, including age-related resistance to insulin signaling, which has been implicated as a mechanism in senescence and neurodegeneration, may contribute[10,19]
We found that expression of PFKFB3 and lactate dehydrogenase A (LDHA) were decreased in old controls and late-onset Alzheimer’s disease (LOAD) cells when compared to young fibroblasts, but they were increased in LOAD compared to healthy old cells (Fig. 6a)
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by slow progressive deterioration and death of neurons. I.e., energy metabolism, are part of the normal aging process and disturbed bioenergetics may be a contributing mechanism underlying LOAD7–10. 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 the underlying causes of bioenergetic dysfunctions in aging and degenerating cells may be in part due to an increase in mitochondrial damage and dysfunction, deficiencies in glucose processing and glycolysis, including age-related resistance to insulin signaling, which has been implicated as a mechanism in senescence and neurodegeneration, may contribute[10,19]. Using a set of skin fibroblast lines, we show that LOAD cells have respiratory deficiencies and exhibit a Warburg-type effect that is disease-specific and unrelated to age, suggesting that bioenergetic abnormalities may be an inherent mechanism underlying LOAD
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