- A disruption in energy production may play a role in the development and advancement of Late-Onset Alzheimer's Disease.
- As Late-Onset Alzheimer's Disease is a disease mainly based on age, thereby all the physiologic changes that occur with age may increase the risk of development of the disease
- Bioenergetics and metabolic changes are some of the main physiological changes associated with age.
- Late-Onset Alzheimer's Disease patients cells have demonstrated an impaired mitochondrial metabolism, with a reduction in number of molecules, that are important in energy production
Disruptions in the bioenergetic mechanism and metabolic changes in the body with age may contribute to the development of Alzheimer's Disease found a new study published in Scientific Reports
"These findings have several implications for understanding and developing potential therapeutic intervention in Late-Onset Alzheimer's Disease (LOAD)," explained Sonntag, an associate stem cell researcher at McLean Hospital and an assistant professor of psychiatry at Harvard Medical School.
‘Late-Onset Alzheimer's Disease patient's fibroblast cells exhibited an impaired mitochondrial metabolism, with a notable reduction in number of energy molecules, that are important in energy production, such as Nicotinamide Adenine Dinucleotide (NAD).’
"Our results support the hypothesis that impairment in multiple interacting components of bioenergetics metabolism may be a key mechanism underlying and contributing to the risk and pathophysiology of this devastating illness."
For three decades, it has been thought that the accumulation of small toxic molecules in the brain, called Amyloid beta, or in short, Aβ is central to the development of Alzheimer's Disease (AD).
Strong evidence came from studying familial or Early-Onset Forms of Alzheimer's Disease(EOAD) that affect about five percent of Alzheimer's Disease patients and have associations with mutations leading to abnormally high levels or abnormal processing of Aβ in the brain.
However, the "Aβ hypothesis" has been insufficient to explain the pathological changes in the more common (LOAD), which affects more than 5 million seniors in the United States.
"Because late-onset Alzheimer's is a disease of age, many physiologic changes with age may contribute to risk for the disease, including changes in bioenergetics and metabolism," said Cohen, director of the Program for Neuropsychiatric Research at McLean Hospital and the Robertson-Steele Professor of Psychiatry at Harvard Medical School.
Bioenergetic Processes Manage the Energy Production and its Exchanges
"Bioenergetics is the production, usage, and exchange of energy within and between cells or organs, and the environment. It has long been known that bioenergetic changes occur with aging and affect the whole body, but more so the brain, with its high need for energy."
According to Sonntag and Cohen, it has been less clear what changes in bioenergetics are underlying and which are a consequence of aging and illness.
Bioenergetic Analysis of Late Onset Alzheimer Disease Patients
In their study, Sonntag and Cohen analyzed the bioenergetic profiles of skin fibroblasts from LOAD patients and healthy controls, as a function of age and disease.
The scientists looked at the two main components that produce energy in cells: glycolysis, which is the mechanism to convert glucose into fuel molecules for consumption by mitochondria, and burning of these fuels in the mitochondria, which use oxygen in a process called oxidative phosphorylation or mitochondrial respiration.
Exhibition of Impaired Mitochondrial Metabolism
The investigators found that LOAD patient's cells exhibited impaired mitochondrial metabolism, with a reduction in number of molecules, that are important in energy production, including Nicotinamide Adenine Dinucleotide (NAD).
LOAD patients fibroblasts also demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to the insulin analog IGF-1.
Both the abnormal mitochondrial metabolism and the increase of glycolysis in LOAD cells were disease- and not age-specific, while diminished glucose uptake and the inability to respond to IGF-1 was a feature of both age and disease.
Fibroblasts of Later Onset Alzheimer Disease Patients Show Deficient Metabolic Mitochondrial Potential
"The observation that LOAD fibroblasts had a deficiency in the mitochondrial metabolic potential and an increase in the glycolytic activity to maintain energy supply is indicative of failing mitochondria and fits with current knowledge that aging cells increasingly suffer from oxidative stress that impairs their mitochondrial energy production," said Sonntag.
Cohen added that because the brain's nerve cells rely almost entirely on mitochondria-derived energy, failure of mitochondrial function, while seen throughout the body, might be particularly detrimental in the brain.
The study's results link to findings from other studies that decreasing energy-related molecules and specifically NAD are features of normal aging by suggesting that abnormalities in processes involving these molecules may also be a factor in neurodegenerative diseases like Late-Onset Alzheimer's Disease.
Whether modulating these compounds could slow the aging process and prevent or delay the onset of LOAD is unknown. However, several clinical trials are currently under way to test this possibility. Other changes are unique to Alzheimer's Disease, and these too, may be targets for intervention.
While these findings are significant, the paper's authors emphasize that the pathogenesis of Late Onset Alzheimer's Disease is multifactorial, with bioenergetics being one part of risk determination and note that the skin fibroblasts studied are not the primary cell type that is affected in Late-Onset Alzheimer's Disease.
"However, because bioenergetics changes are body-wise, observations made in fibroblasts may also be relevant to brain cells," said Sonntag.
"In fact, metabolic changes like diminished glucose uptake and insulin/IGF-1 resistance may underlie the association between various disorders of aging, such as type 2 diabetes and Alzheimer disease."
Sonntag and Cohen are already in the midst of follow-up work aiming to study these bioenergetics features in brain nerve cells and astrocytes generated from LOAD patient-derived induced pluripotent stem cells, as an aging and disease model in the dish.
It is the group's hope that findings from these studies will reveal further insight into the role of bioenergetics in LOAD pathogenesis and novel targets for intervention--both prevention and treatment.
- Kai-C. Sonntag, Woo-In Ryu, Kristopher M. Amirault, Ryan A. Healy, Arthur J. Siegel, Donna L. McPhie, Brent Forester & Bruce M. Cohen. Late-onset Alzheimer's disease is associated with inherent changes in bioenergetics profiles, Scientific Reports; (October 2017).doi:10.1038/s41598-017-14420-x