Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer's Disease

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Jan 22

PMID 38247880

Authors

Song-I Seol

Dashdulam Davaanyam

Sang-A Oh

Eun-Hwa Lee

Pyung-Lim Han

Seung-Woo Kim

Ja-Kyeong Lee

Affiliations

Soon will be listed here.

Abstract

HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer's disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in relation to the pathology of Alzheimer's disease has not yet been studied in detail. Here, we investigated whether HMGB1 protein levels in brain tissue homogenates (frontal cortex and striatum) and sera from Tg-APP/PS1 mice, along with its cellular and subcellular localization in those regions, differed. Total HMGB1 levels were increased in the frontal cortices of aged wildtype (7.5 M) mice compared to young (3.5 M) mice, whereas total HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice (7.5 M) were significantly lower than those in age-matched wildtype mice. In contrast, total serum HMGB1 levels were enhanced in aged wildtype (7.5 M) mice and Tg-APP/PS1 mice (7.5 M). Further analysis indicated that nuclear HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice were significantly reduced compared to those in age-matched wildtype controls, and cytosolic HMGB1 levels were also significantly decreased. Triple-fluorescence immunohistochemical analysis indicated that HMGB1 appeared as a ring shape in the cytoplasm of most neurons and microglia in the frontal cortices of 9.5 M Tg-APP/PS1 mice, indicating that nuclear HMGB1 is reduced by aging and in Tg-APP/PS1 mice. Consistent with these observations, Aβ treatment of both primary cortical neuron and primary microglial cultures increased HMGB1 secretion in the media, in an Aβ-dose-dependent manner. Our results indicate that nuclear HMGB1 might be translocated from the nucleus to the cytoplasm in both neurons and microglia in the brains of Tg-APP/PS1 mice, and that it may subsequently be secreted extracellularly.

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References

Frank M, Weber M, Watkins L, Maier S . Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. Brain Behav Immun. 2015; 48:1-7. PMC: 4508196. DOI: 10.1016/j.bbi.2015.03.010. View

Limbad C, Ronnen Oron T, Alimirah F, Davalos A, Tracy T, Gan L . Astrocyte senescence promotes glutamate toxicity in cortical neurons. PLoS One. 2020; 15(1):e0227887. PMC: 6964973. DOI: 10.1371/journal.pone.0227887. View

Venereau E, Casalgrandi M, Schiraldi M, Antoine D, Cattaneo A, De Marchis F . Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med. 2012; 209(9):1519-28. PMC: 3428943. DOI: 10.1084/jem.20120189. View

Muller S, Scaffidi P, Degryse B, Bonaldi T, Ronfani L, Agresti A . New EMBO members' review: the double life of HMGB1 chromatin protein: architectural factor and extracellular signal. EMBO J. 2001; 20(16):4337-40. PMC: 125571. DOI: 10.1093/emboj/20.16.4337. View

Gao J, Zhang X, Shu G, Chen N, Zhang J, Xu F . Trilobatin rescues cognitive impairment of Alzheimer's disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway. Acta Pharmacol Sin. 2022; 43(10):2482-2494. PMC: 9525711. DOI: 10.1038/s41401-022-00888-5. View

Shao P . MiR-216a-5p ameliorates learning-memory deficits and neuroinflammatory response of Alzheimer's disease mice via regulation of HMGB1/NF-κB signaling. Brain Res. 2021; 1766:147511. DOI: 10.1016/j.brainres.2021.147511. View

Kim I, Lee H, Kim S, Lee H, Choi J, Han P . Alarmin HMGB1 induces systemic and brain inflammatory exacerbation in post-stroke infection rat model. Cell Death Dis. 2018; 9(4):426. PMC: 5859283. DOI: 10.1038/s41419-018-0438-8. View

Itkin A, Dupres V, Dufrene Y, Bechinger B, Ruysschaert J, Raussens V . Calcium ions promote formation of amyloid β-peptide (1-40) oligomers causally implicated in neuronal toxicity of Alzheimer's disease. PLoS One. 2011; 6(3):e18250. PMC: 3065491. DOI: 10.1371/journal.pone.0018250. View

Takata K, Kitamura Y, Tsuchiya D, Kawasaki T, Taniguchi T, Shimohama S . High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity. J Neurosci Res. 2004; 78(6):880-91. DOI: 10.1002/jnr.20340. View

10.

Wahlster L, Arimon M, Nasser-Ghodsi N, Post K, Serrano-Pozo A, Uemura K . Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease. Acta Neuropathol. 2012; 125(2):187-99. PMC: 3552123. DOI: 10.1007/s00401-012-1065-6. View

11.

Enokido Y, Yoshitake A, Ito H, Okazawa H . Age-dependent change of HMGB1 and DNA double-strand break accumulation in mouse brain. Biochem Biophys Res Commun. 2008; 376(1):128-33. DOI: 10.1016/j.bbrc.2008.08.108. View

12.

Takata K, Takada T, Ito A, Asai M, Tawa M, Saito Y . Microglial Amyloid-β1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer's Disease. Int J Alzheimers Dis. 2012; 2012:685739. PMC: 3357001. DOI: 10.1155/2012/685739. View

13.

Jang A, Liew H, Kim Y, Choi H, Kim S, Lee S . p35 deficiency accelerates HMGB-1-mediated neuronal death in the early stages of an Alzheimer's disease mouse model. Curr Alzheimer Res. 2013; 10(8):829-43. DOI: 10.2174/15672050113109990135. View

14.

Jucker M, Walker L . Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013; 501(7465):45-51. PMC: 3963807. DOI: 10.1038/nature12481. View

15.

Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S . Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nat Struct Mol Biol. 2010; 17(5):561-7. PMC: 2922021. DOI: 10.1038/nsmb.1799. View

16.

Gaikwad S, Puangmalai N, Bittar A, Montalbano M, Garcia S, McAllen S . Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia. Cell Rep. 2021; 36(3):109419. PMC: 8341760. DOI: 10.1016/j.celrep.2021.109419. View

17.

Zhou Z, Hou J, Mo Y, Ren M, Yang G, Qu Z . Geniposidic acid ameliorates spatial learning and memory deficits and alleviates neuroinflammation via inhibiting HMGB-1 and downregulating TLR4/2 signaling pathway in APP/PS1 mice. Eur J Pharmacol. 2019; 869:172857. DOI: 10.1016/j.ejphar.2019.172857. View

18.

Fonken L, Frank M, Kitt M, DAngelo H, Norden D, Weber M . The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming. J Neurosci. 2016; 36(30):7946-56. PMC: 4961779. DOI: 10.1523/JNEUROSCI.1161-16.2016. View

19.

Davalos A, Kawahara M, Malhotra G, Schaum N, Huang J, Ved U . p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol. 2013; 201(4):613-29. PMC: 3653366. DOI: 10.1083/jcb.201206006. View

20.

Heneka M, Carson M, El Khoury J, Landreth G, Brosseron F, Feinstein D . Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015; 14(4):388-405. PMC: 5909703. DOI: 10.1016/S1474-4422(15)70016-5. View