Imagine if the human body was a car engine. Just as gasoline powers the engine, certain substances called glycocholic acid (GCA) and linoleic acid (LA) play a role in fueling our brain cells. In a recent study, researchers investigated how these two substances are linked to mitochondrial bioenergetics, which are alterations that occur in patients with Alzheimer’s disease. The study focused on plasma circulating factors, specifically lipids, as potential mediators of bioenergetic differences in participants with normal cognition, mild cognitive impairment, and dementia due to probable AD. By measuring mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and exposing neuronal cells to plasma from different cognitive groups, the researchers discovered that GCA correlated positively with PBMC and neuronal bioenergetics, while LA showed a negative correlation. These findings suggest that GCA and LA may contribute to the stimulatory and inhibitory effects on bioenergetics seen in different cognitive states. Further analysis confirmed that GCA levels were significantly lower in dementia patients compared to those with normal cognition, while LA levels were higher. The study highlights the direct impact of circulating factors on mitochondrial bioenergetics and provides valuable insights into the metabolic changes associated with Alzheimer’s disease. To learn more about this research and its implications, check out the full article!

Mitochondrial bioenergetic alterations occur in the brain and peripheral cells of patients with Alzheimer’s disease (AD). This study focuses on plasma circulating factors, namely lipids, as mediators of systemic bioenergetic differences in participants with normal cognition (NC), mild cognitive impairment (MCI), and dementia due to probable AD (DEM). We examined bioenergetic differences across cognitive groups by measuring the mitochondrial respiration of peripheral blood mononuclear cells (PBMCs) from 37 participants (12 NC, 12 MCI, 13 DEM). PBMC bioenergetics were lower in the DEM group compared to the NC group. To determine whether circulating factors can mediate bioenergetic differences according to cognitive status, we exposed naïve neuronal Neuro-2a (N2a) cells to plasma from each participant in vitro. N2a bioenergetics were lower following plasma exposure from DEM compared to NC group participants. Notably, PBMC Max and N2a Max positively correlated, suggesting that circulating factors modulate the bioenergetics of naïve N2a cells according to the bioenergetic capacity of donor primary PBMCs. To identify lipid metabolites that may contribute to bioenergetic differences between cognitive groups, we performed liquid chromatography-mass spectrometry to assess the abundance of individual lipid species and correlated PBMC and N2a bioenergetics. Glycocholic acid (GCA) positively correlated with PBMC and N2a bioenergetics, while linoleic acid (LA) was negatively correlated. These data suggest that GCA and LA may contribute to the stimulatory and inhibitory bioenergetics effects related to cognitive status. Post hoc analyses revealed that GCA abundance was lower by 52.9% in the DEM group compared to the NC group and that LA abundance was higher by 55.7% in the DEM group compared to the NC group. To validate these findings, we examined the abundance of GCA and LA in the larger, more diverse, parent cohort (n = 378) and found similar results; GCA abundance was lower by 29.7% in the DEM group compared to the NC group and LA abundance was higher by 17.8% in the DEM group compared to the NC group. These data demonstrate that circulating factors have a direct effect on mitochondrial bioenergetics and that individual circulating factors identified to be associated with mitochondrial function are differentially expressed in patients with dementia.

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