The Expression Pattern of GDF15 in Human Brain Changes During Aging and in Alzheimer's Disease

Overview

Journal Front Aging Neurosci

Specialty Geriatrics

Date 2023 Jan 26

PMID 36698863

Authors

Antonio Chiariello

Sabrina Valente

Gianandrea Pasquinelli

Alessandra Baracca

Gianluca Sgarbi

Giancarlo Solaini

Valentina Medici

Valentina Fantini

Tino Emanuele Poloni

Monica Tognocchi

Marina Arcaro

Daniela Galimberti

Claudio Franceschi

Miriam Capri

Stefano Salvioli

Maria Conte

Affiliations

Soon will be listed here.

Abstract

Introduction: Growth Differentiation Factor 15 (GDF15) is a mitochondrial-stress-responsive molecule whose expression strongly increases with aging and age-related diseases. However, its role in neurodegenerative diseases, including Alzheimer's disease (AD), is still debated.

Methods: We have characterized the expression of GDF15 in brain samples from AD patients and non-demented subjects (controls) of different ages.

Results: Although no difference in CSF levels of GDF15 was found between AD patients and controls, GDF15 was expressed in different brain areas and seems to be predominantly localized in neurons. The ratio between its mature and precursor form was higher in the frontal cortex of AD patients compared to age-matched controls ( < 0.05). Moreover, this ratio was even higher for centenarians ( < 0.01), indicating that aging also affects GDF15 expression and maturation. A lower expression of OXPHOS complexes I, III, and V in AD patients compared to controls was also noticed, and a positive correlation between and mRNA levels was observed. Finally, when GDF15 was silenced in dermal fibroblasts, a decrease in OXPHOS complexes transcript levels and an increase in levels were observed.

Discussion: Although GDF15 seems not to be a reliable CSF marker for AD, it is highly expressed in aging and AD brains, likely as a part of stress response aimed at counteracting mitochondrial dysfunction and neuroinflammation.

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References

Chung H, Kim J, Kim H, Kwon M, Kim S, Shong M . GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep. 2017; 7(1):17238. PMC: 5722931. DOI: 10.1038/s41598-017-17574-w. View

Pradeepkiran J, Reddy P . Defective mitophagy in Alzheimer's disease. Ageing Res Rev. 2020; 64:101191. PMC: 7710581. DOI: 10.1016/j.arr.2020.101191. View

Perez M, Ponce D, Osorio-Fuentealba C, Behrens M, Quintanilla R . Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease. Front Neurosci. 2017; 11:553. PMC: 5635042. DOI: 10.3389/fnins.2017.00553. View

Baleriola J, Walker C, Jean Y, Crary J, Troy C, Nagy P . Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell. 2014; 158(5):1159-1172. PMC: 4149755. DOI: 10.1016/j.cell.2014.07.001. View

Li J, Liu J, Lupino K, Liu X, Zhang L, Pei L . Growth Differentiation Factor 15 Maturation Requires Proteolytic Cleavage by PCSK3, -5, and -6. Mol Cell Biol. 2018; 38(21). PMC: 6189459. DOI: 10.1128/MCB.00249-18. View

Gauthier S, Albert M, Fox N, Goedert M, Kivipelto M, Mestre-Ferrandiz J . Why has therapy development for dementia failed in the last two decades?. Alzheimers Dement. 2015; 12(1):60-4. DOI: 10.1016/j.jalz.2015.12.003. View

Erickson M, Banks W . Age-Associated Changes in the Immune System and Blood⁻Brain Barrier Functions. Int J Mol Sci. 2019; 20(7). PMC: 6479894. DOI: 10.3390/ijms20071632. View

Wischhusen J, Melero I, Fridman W . Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol. 2020; 11:951. PMC: 7248355. DOI: 10.3389/fimmu.2020.00951. View

Chai Y, Hilal S, Chong J, Ng Y, Liew O, Xu X . Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia. Medicine (Baltimore). 2016; 95(33):e4566. PMC: 5370808. DOI: 10.1097/MD.0000000000004566. View

10.

Kim D, Lee D, Chang E, Kim J, Hwang J, Kim J . GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model. Stem Cells Dev. 2015; 24(20):2378-90. PMC: 4598918. DOI: 10.1089/scd.2014.0487. View

11.

Hooper C, Meimaridou E, Tavassoli M, Melino G, Lovestone S, Killick R . p53 is upregulated in Alzheimer's disease and induces tau phosphorylation in HEK293a cells. Neurosci Lett. 2007; 418(1):34-7. PMC: 1885960. DOI: 10.1016/j.neulet.2007.03.026. View

12.

Holper L, Ben-Shachar D, Mann J . Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease. Neuropsychopharmacology. 2018; 44(5):837-849. PMC: 6461987. DOI: 10.1038/s41386-018-0090-0. View

13.

Mufson E, Binder L, Counts S, DeKosky S, de Toledo-Morrell L, Ginsberg S . Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol. 2011; 123(1):13-30. PMC: 3282485. DOI: 10.1007/s00401-011-0884-1. View

14.

Kim D, Lee D, Lim H, Choi S, Oh W, Yang Y . Effect of growth differentiation factor-15 secreted by human umbilical cord blood-derived mesenchymal stem cells on amyloid beta levels in in vitro and in vivo models of Alzheimer's disease. Biochem Biophys Res Commun. 2018; 504(4):933-940. DOI: 10.1016/j.bbrc.2018.09.012. View

15.

Melber A, Haynes C . UPR regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res. 2018; 28(3):281-295. PMC: 5835775. DOI: 10.1038/cr.2018.16. View

16.

Montero R, Yubero D, Villarroya J, Henares D, Jou C, Rodriguez M . GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016; 11(2):e0148709. PMC: 4750949. DOI: 10.1371/journal.pone.0148709. View

17.

Carrillo-Garcia C, Prochnow S, Simeonova I, Strelau J, Holzl-Wenig G, Mandl C . Growth/differentiation factor 15 promotes EGFR signalling, and regulates proliferation and migration in the hippocampus of neonatal and young adult mice. Development. 2014; 141(4):773-83. PMC: 3930467. DOI: 10.1242/dev.096131. View

18.

Yang H, Park S, Choi H, Moon Y . The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-beta). Carcinogenesis. 2010; 31(4):703-11. DOI: 10.1093/carcin/bgq008. View

19.

Kim H, Kim K, Kang M, Lim S . Growth differentiation factor-15 as a biomarker for sarcopenia in aging humans and mice. Exp Gerontol. 2020; 142:111115. DOI: 10.1016/j.exger.2020.111115. View

20.

Lehallier B, Gate D, Schaum N, Nanasi T, Lee S, Yousef H . Undulating changes in human plasma proteome profiles across the lifespan. Nat Med. 2019; 25(12):1843-1850. PMC: 7062043. DOI: 10.1038/s41591-019-0673-2. View