Byrns CN, Perlegos AE, Miller KN, Jin Z, Carranza FR, Manchandra P, Beveridge CH, Randolph CE, Chaluvadi VS, Zhang SL, Srinivasan AR, Bennett FC, Sehgal A, Adams PD, Chopra G, Bonini NM. Senescent glia link mitochondrial dysfunction and lipid accumulation. Nature. 2024 Jun 5; PubMed.
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Baylor College of Medicine/TCH
Baylor College of Medicine
Baylor College of Medicine
This exciting work helps tie together several independent areas of research, including cellular senescence, lipid droplet formation, and mitochondrial dysfunction during aging. It has been previously reported that glia accumulate lipid droplets in response to oxidative stress in neurons (Moulton et al., 2021; Liu et al., 2015; Ioannou et al., 2019; Goodman et al., in press), and that oxidative radical levels increase with age and in AD (Grimm and Eckert, 2017; Butterfield, 2020; Peña-Bautista et al., 2019). Further, it has been hypothesized that increased glial senescence drives AD pathology, additional senescence, and the transition from MCI to AD (Lau et al., 2023).
This work provides mechanistic insight into a trigger of glial senescence via mitochondrial dysfunction in neurons. Importantly, the authors found that glial senescence markers were reduced when animals were treated with the antioxidant N-acetylcysteine amide (NACA or AD4), the same compound we and others found limits lipid peroxidation, and subsequent glial lipid droplet accumulation, as well as prevent neurodegeneration (Moulton et al., 2021; Liu et al., 2015; Goodman et al. (in press); Chung et al., 2020; Schimel et al., 2011), providing support for the use of NACA to prevent age-associated cellular toxicities.
The authors provide evidence that lipid droplets that accumulate in aged brains are sourced by lipids from the senescent glia themselves (cell autonomous), while others suggest that the source of glial lipid droplets in young brains is neurons (non-cell autonomous) (Moulton et al., 2021; Liu et al., 2015; Liu et al., 2017). Thus, it will be important to delineate the role of each cell type throughout the aging process and to understand the key impacts (protective and deleterious) that cell-autonomous and non-cell-autonomous glial lipid droplet formation may have on aging and disease. Furthermore, this pathway has been demonstrated to regulate sleep (Haynes et al., 2024), perhaps explaining sleep dysregulation seen in aging and AD patients (Goodman et al., 2024).
References:
Moulton MJ, Barish S, Ralhan I, Chang J, Goodman LD, Harland JG, Marcogliese PC, Johansson JO, Ioannou MS, Bellen HJ. Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer's disease-associated genes. Proc Natl Acad Sci U S A. 2021 Dec 28;118(52) PubMed.
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