Increased Expression of Transferrin Receptor 1 in the Brain Cortex of 5xFAD Mouse Model of Alzheimer's Disease Is Associated with Activation of HIF-1 Signaling Pathway.
5xFAD mice
Alzheimer’s disease
Brain cortex
Brain microvessels
HIF-1
Transferrin receptor
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
01 Feb 2024
01 Feb 2024
Historique:
received:
19
11
2023
accepted:
24
01
2024
medline:
1
2
2024
pubmed:
1
2
2024
entrez:
31
1
2024
Statut:
aheadofprint
Résumé
Alzheimer's disease (AD) is the most common cause of dementia. Despite intensive research efforts, there are currently no effective treatments to cure and prevent AD. There is growing evidence that dysregulation of iron homeostasis may contribute to the pathogenesis of AD. Given the important role of the transferrin receptor 1 (TfR1) in regulating iron distribution in the brain, as well as in the drug delivery, we investigated its expression in the brain cortex and isolated brain microvessels from female 8-month-old 5xFAD mice mimicking advanced stage of AD. Moreover, we explored the association between the TfR1 expression and the activation of the HIF-1 signaling pathway, as well as oxidative stress and inflammation in 5xFAD mice. Finally, we studied the impact of Aβ
Identifiants
pubmed: 38296900
doi: 10.1007/s12035-024-03990-3
pii: 10.1007/s12035-024-03990-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Brandsma ME, Jevnikar AM, Ma S (2011) Recombinant human transferrin: beyond iron binding and transport. Biotechnol Adv 29(2):230–238. https://doi.org/10.1016/j.biotechadv.2010.11.007
doi: 10.1016/j.biotechadv.2010.11.007
pubmed: 21147210
Leitner DF, Connor JR (2012) Functional roles of transferrin in the brain. Biochim Biophys Acta 1820(3):393–402. https://doi.org/10.1016/j.bbagen.2011.10.016
doi: 10.1016/j.bbagen.2011.10.016
pubmed: 22138408
Nielsen SSE, Holst MR, Langthaler K, Christensen SC, Bruun EH, Brodin B, Nielsen MS (2023) Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells. Fluids Barriers CNS 20(1):2. https://doi.org/10.1186/s12987-022-00404-1
doi: 10.1186/s12987-022-00404-1
pubmed: 36624498
pmcid: 9830855
Huwyler J, Pardridge WM (1998) Examination of blood-brain barrier transferrin receptor by confocal fluorescent microscopy of unfixed isolated rat brain capillaries. J Neurochem 70(2):883–886. https://doi.org/10.1046/j.1471-4159.1998.70020883.x
doi: 10.1046/j.1471-4159.1998.70020883.x
pubmed: 9453586
Lu CD, Ma JK, Luo ZY, Tai QX, Wang P, Guan PP (2018) Transferrin is responsible for mediating the effects of iron ions on the regulation of anterior pharynx-defective-1alpha/beta and Presenilin 1 expression via PGE(2) and PGD(2) at the early stage of Alzheimer’s disease. Aging (Albany NY) 10 (11):3117–3135. https://doi.org/10.18632/aging.101615
Khan AI, Liu J, Dutta P (2018) Iron transport kinetics through blood-brain barrier endothelial cells. Biochim Biophys Acta Gen Subj 1862(5):1168–1179. https://doi.org/10.1016/j.bbagen.2018.02.010
doi: 10.1016/j.bbagen.2018.02.010
pubmed: 29466707
Johnsen KB, Burkhart A, Melander F, Kempen PJ, Vejlebo JB, Siupka P, Nielsen MS, Andresen TL, Moos T (2017) Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma. Sci Rep 7(1):10396. https://doi.org/10.1038/s41598-017-11220-1
doi: 10.1038/s41598-017-11220-1
pubmed: 28871203
pmcid: 5583399
Campos-Escamilla C (2021) The role of transferrins and iron-related proteins in brain iron transport: applications to neurological diseases. Adv Protein Chem Struct Biol 123:133–162. https://doi.org/10.1016/bs.apcsb.2020.09.002
doi: 10.1016/bs.apcsb.2020.09.002
pubmed: 33485481
Moos T, Morgan EH (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 20(1):77–95. https://doi.org/10.1023/a:1006948027674
doi: 10.1023/a:1006948027674
pubmed: 10690503
Paterson J, Webster CI (2016) Exploiting transferrin receptor for delivering drugs across the blood-brain barrier. Drug Discov Today Technol 20:49–52. https://doi.org/10.1016/j.ddtec.2016.07.009
doi: 10.1016/j.ddtec.2016.07.009
pubmed: 27986223
Pulgar VM (2018) Transcytosis to cross the blood brain barrier, new advancements and challenges. Front Neurosci 12:1019. https://doi.org/10.3389/fnins.2018.01019
doi: 10.3389/fnins.2018.01019
pubmed: 30686985
Johnsen KB, Burkhart A, Thomsen LB, Andresen TL, Moos T (2019) Targeting the transferrin receptor for brain drug delivery. Prog Neurobiol 181:101665. https://doi.org/10.1016/j.pneurobio.2019.101665
doi: 10.1016/j.pneurobio.2019.101665
pubmed: 31376426
Thomsen MS, Johnsen KB, Kucharz K, Lauritzen M, Moos T (2022) Blood-brain barrier transport of transferrin receptor-targeted nanoparticles. Pharmaceutics 14(10). https://doi.org/10.3390/pharmaceutics14102237
Wang F, Wang J, Shen Y, Li H, Rausch WD, Huang X (2022) Iron dyshomeostasis and ferroptosis: a new Alzheimer’s disease hypothesis? Front Aging Neurosci 14:830569. https://doi.org/10.3389/fnagi.2022.830569
doi: 10.3389/fnagi.2022.830569
pubmed: 35391749
pmcid: 8981915
Wu L, Xian X, Tan Z, Dong F, Xu G, Zhang M, Zhang F (2023) The role of iron metabolism, lipid metabolism, and redox homeostasis in Alzheimer’s disease: from the perspective of ferroptosis. Mol Neurobiol 60(5):2832–2850. https://doi.org/10.1007/s12035-023-03245-7
doi: 10.1007/s12035-023-03245-7
pubmed: 36735178
Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y (2020) Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener 15(1):40. https://doi.org/10.1186/s13024-020-00391-7
doi: 10.1186/s13024-020-00391-7
pubmed: 32677986
pmcid: 7364557
Cahill CM, Lahiri DK, Huang X, Rogers JT (2009) Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases. Biochim Biophys Acta 1790(7):615–628. https://doi.org/10.1016/j.bbagen.2008.12.001
doi: 10.1016/j.bbagen.2008.12.001
pubmed: 19166904
Tao Y, Wang Y, Rogers JT, Wang F (2014) Perturbed iron distribution in Alzheimer’s disease serum, cerebrospinal fluid, and selected brain regions: a systematic review and meta-analysis. J Alzheimers Dis 42(2):679–690. https://doi.org/10.3233/JAD-140396
doi: 10.3233/JAD-140396
pubmed: 24916541
Raven EP, Lu PH, Tishler TA, Heydari P, Bartzokis G (2013) Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer’s disease detected in vivo with magnetic resonance imaging. J Alzheimers Dis 37(1):127–136. https://doi.org/10.3233/JAD-130209
doi: 10.3233/JAD-130209
pubmed: 23792695
Peng Y, Chang X, Lang M (2021) Iron homeostasis disorder and Alzheimer’s disease. Int J Mol Sci 22(22). https://doi.org/10.3390/ijms222212442
Bourassa P, Alata W, Tremblay C, Paris-Robidas S, Calon F (2019) Transferrin receptor-mediated uptake at the blood-brain barrier is not impaired by Alzheimer’s disease neuropathology. Mol Pharm 16(2):583–594. https://doi.org/10.1021/acs.molpharmaceut.8b00870
doi: 10.1021/acs.molpharmaceut.8b00870
pubmed: 30609376
Kalaria RN, Sromek SM, Grahovac I, Harik SI (1992) Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer’s disease. Brain Res 585(1–2):87–93. https://doi.org/10.1016/0006-8993(92)91193-i
doi: 10.1016/0006-8993(92)91193-i
pubmed: 1511337
Lu LN, Qian ZM, Wu KC, Yung WH, Ke Y (2017) Expression of iron transporters and pathological hallmarks of Parkinson’s and Alzheimer’s diseases in the brain of young, adult, and aged rats. Mol Neurobiol 54(7):5213–5224. https://doi.org/10.1007/s12035-016-0067-0
doi: 10.1007/s12035-016-0067-0
pubmed: 27578012
Huang XT, Qian ZM, He X, Gong Q, Wu KC, Jiang LR, Lu LN, Zhu ZJ, Zhang HY, Yung WH, Ke Y (2014) Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer’s disease. Neurobiol Aging 35(5):1045–1054. https://doi.org/10.1016/j.neurobiolaging.2013.11.004
doi: 10.1016/j.neurobiolaging.2013.11.004
pubmed: 24332448
Tacchini L, Gammella E, De Ponti C, Recalcati S, Cairo G (2008) Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. J Biol Chem 283(30):20674–20686. https://doi.org/10.1074/jbc.M800365200
doi: 10.1074/jbc.M800365200
pubmed: 18519569
pmcid: 3258948
Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274(34):24147–24152. https://doi.org/10.1074/jbc.274.34.24147
doi: 10.1074/jbc.274.34.24147
pubmed: 10446188
Dery MA, Michaud MD, Richard DE (2005) Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 37(3):535–540. https://doi.org/10.1016/j.biocel.2004.08.012
doi: 10.1016/j.biocel.2004.08.012
pubmed: 15618010
Maki T, Sawahata M, Akutsu I, Amaike S, Hiramatsu G, Uta D, Izuo N, Shimizu T, Irie K, Kume T (2022) APP knock-in mice produce E22P-abeta exhibiting an Alzheimer’s disease-like phenotype with dysregulation of hypoxia-inducible factor expression. Int J Mol Sci 23(21). https://doi.org/10.3390/ijms232113259
Ashok BS, Ajith TA, Sivanesan S (2017) Hypoxia-inducible factors as neuroprotective agent in Alzheimer’s disease. Clin Exp Pharmacol Physiol 44(3):327–334. https://doi.org/10.1111/1440-1681.12717
doi: 10.1111/1440-1681.12717
pubmed: 28004401
Merelli A, Rodriguez JCG, Folch J, Regueiro MR, Camins A, Lazarowski A (2018) Understanding the role of hypoxia inducible factor during neurodegeneration for new therapeutics opportunities. Curr Neuropharmacol 16(10):1484–1498. https://doi.org/10.2174/1570159X16666180110130253
doi: 10.2174/1570159X16666180110130253
pubmed: 29318974
pmcid: 6295932
Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A, Bourdoulous S, Turowski P, Male DK, Roux F, Greenwood J, Romero IA, Couraud PO (2005) Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19(13):1872–1874. https://doi.org/10.1096/fj.04-3458fje
doi: 10.1096/fj.04-3458fje
pubmed: 16141364
Ohtsuki S, Ikeda C, Uchida Y, Sakamoto Y, Miller F, Glacial F, Decleves X, Scherrmann JM, Couraud PO, Kubo Y, Tachikawa M, Terasaki T (2013) Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model. Mol Pharm 10(1):289–296. https://doi.org/10.1021/mp3004308
doi: 10.1021/mp3004308
pubmed: 23137377
Puris E, Saveleva L, de Sousa MI, Kanninen KM, Auriola S, Fricker G (2023) Protein expression of amino acid transporters is altered in isolated cerebral microvessels of 5xFAD mouse model of Alzheimer’s disease. Mol Neurobiol 60(2):732–748. https://doi.org/10.1007/s12035-022-03111-y
doi: 10.1007/s12035-022-03111-y
pubmed: 36367657
Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O (2012) Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging 33(1):196 e129–140. https://doi.org/10.1016/j.neurobiolaging.2010.05.027
Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Goldstein JM, Kantarci K, Mallampalli MP, Mormino EC, Scott L, Yu WH, Maki PM, Mielke MM (2018) Understanding the impact of sex and gender in Alzheimer’s disease: a call to action. Alzheimers Dement 14(9):1171–1183. https://doi.org/10.1016/j.jalz.2018.04.008
doi: 10.1016/j.jalz.2018.04.008
pubmed: 29907423
pmcid: 6400070
Oblak AL, Lin PB, Kotredes KP, Pandey RS, Garceau D, Williams HM, Uyar A, O’Rourke R, O’Rourke S, Ingraham C, Bednarczyk D, Belanger M, Cope ZA, Little GJ, Williams SG, Ash C, Bleckert A, Ragan T, Logsdon BA, Mangravite LM, Sukoff Rizzo SJ, Territo PR, Carter GW, Howell GR, Sasner M, Lamb BT (2021) Comprehensive evaluation of the 5XFAD mouse model for preclinical testing applications: a MODEL-AD study. Front Aging Neurosci 13:713726. https://doi.org/10.3389/fnagi.2021.713726
doi: 10.3389/fnagi.2021.713726
pubmed: 34366832
pmcid: 8346252
Shin J, Park S, Lee H, Kim Y (2021) Thioflavin-positive tau aggregates complicating quantification of amyloid plaques in the brain of 5XFAD transgenic mouse model. Sci Rep 11(1):1617. https://doi.org/10.1038/s41598-021-81304-6
doi: 10.1038/s41598-021-81304-6
pubmed: 33452414
pmcid: 7810901
Forner S, Kawauchi S, Balderrama-Gutierrez G, Kramar EA, Matheos DP, Phan J, Javonillo DI, Tran KM, Hingco E, da Cunha C, Rezaie N, Alcantara JA, Baglietto-Vargas D, Jansen C, Neumann J, Wood MA, MacGregor GR, Mortazavi A, Tenner AJ, LaFerla FM, Green KN (2021) Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease. Sci Data 8(1):270. https://doi.org/10.1038/s41597-021-01054-y
doi: 10.1038/s41597-021-01054-y
pubmed: 34654824
pmcid: 8519958
Shukla V, Zheng YL, Mishra SK, Amin ND, Steiner J, Grant P, Kesavapany S, Pant HC (2013) A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice. FASEB J 27(1):174–186. https://doi.org/10.1096/fj.12-217497
doi: 10.1096/fj.12-217497
pubmed: 23038754
pmcid: 3528323
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26(40):10129–10140. https://doi.org/10.1523/JNEUROSCI.1202-06.2006
doi: 10.1523/JNEUROSCI.1202-06.2006
pubmed: 17021169
pmcid: 6674618
Puris E, Auriola S, Petralla S, Hartman R, Gynther M, de Lange ECM, Fricker G (2022) Altered protein expression of membrane transporters in isolated cerebral microvessels and brain cortex of a rat Alzheimer’s disease model. Neurobiol Dis 169:105741. https://doi.org/10.1016/j.nbd.2022.105741
doi: 10.1016/j.nbd.2022.105741
pubmed: 35472634
Balzer V, Poc P, Puris E, Martin S, Aliasgari M, Auriola S, Fricker G (2022) Re-evaluation of the hCMEC/D3 based in vitro BBB model for ABC transporter studies. Eur J Pharm Biopharm 173:12–21. https://doi.org/10.1016/j.ejpb.2022.02.017
doi: 10.1016/j.ejpb.2022.02.017
pubmed: 35227855
Taylor SC, Nadeau K, Abbasi M, Lachance C, Nguyen M, Fenrich J (2019) The ultimate qPCR experiment: producing publication quality, reproducible data the first time. Trends Biotechnol 37(7):761–774. https://doi.org/10.1016/j.tibtech.2018.12.002
doi: 10.1016/j.tibtech.2018.12.002
pubmed: 30654913
Prakash A, Dhaliwal GK, Kumar P, Majeed AB (2017) Brain biometals and Alzheimer’s disease - boon or bane? Int J Neurosci 127(2):99–108. https://doi.org/10.3109/00207454.2016.1174118
doi: 10.3109/00207454.2016.1174118
pubmed: 27044501
Bartzokis G, Sultzer D, Mintz J, Holt LE, Marx P, Phelan CK, Marder SR (1994) In vivo evaluation of brain iron in Alzheimer’s disease and normal subjects using MRI. Biol Psychiatry 35(7):480–487. https://doi.org/10.1016/0006-3223(94)90047-7
doi: 10.1016/0006-3223(94)90047-7
pubmed: 8018799
Bourassa MW, Leskovjan AC, Tappero RV, Farquhar ER, Colton CA, Van Nostrand WE, Miller LM (2013) Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer’s disease that exhibit neurodegeneration. Biomed Spectrosc Imaging 2(2):129–139. https://doi.org/10.3233/BSI-130041
doi: 10.3233/BSI-130041
pubmed: 24926425
pmcid: 4051362
Belaya I, Kucharikova N, Gorova V, Kysenius K, Hare DJ, Crouch PJ, Malm T, Atalay M, White AR, Liddell JR, Kanninen KM (2021) Regular physical exercise modulates iron homeostasis in the 5xFAD mouse model of Alzheimer’s disease. Int J Mol Sci 22(16). https://doi.org/10.3390/ijms22168715
Peters DG, Connor JR, Meadowcroft MD (2015) The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer’s disease: two sides of the same coin. Neurobiol Dis 81:49–65. https://doi.org/10.1016/j.nbd.2015.08.007
doi: 10.1016/j.nbd.2015.08.007
pubmed: 26303889
pmcid: 4672943
Solovyev N, El-Khatib AH, Costas-Rodriguez M, Schwab K, Griffin E, Raab A, Platt B, Theuring F, Vogl J, Vanhaecke F (2021) Cu, Fe, and Zn isotope ratios in murine Alzheimer’s disease models suggest specific signatures of amyloidogenesis and tauopathy. J Biol Chem 296:100292. https://doi.org/10.1016/j.jbc.2021.100292
doi: 10.1016/j.jbc.2021.100292
pubmed: 33453282
pmcid: 7949056
Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G (1999) Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem 274(34):24142–24146. https://doi.org/10.1074/jbc.274.34.24142
doi: 10.1074/jbc.274.34.24142
pubmed: 10446187
Guo C, Zhang YX, Wang T, Zhong ML, Yang ZH, Hao LJ, Chai R, Zhang S (2015) Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1alpha pathway on the brain of APP/PS1 transgenic mice. Front Aging Neurosci 7:104. https://doi.org/10.3389/fnagi.2015.00104
doi: 10.3389/fnagi.2015.00104
pubmed: 26082716
pmcid: 4451419
Lee DW, Andersen JK (2006) Role of HIF-1 in iron regulation: potential therapeutic strategy for neurodegenerative disorders. Curr Mol Med 6(8):883–893. https://doi.org/10.2174/156652406779010849
doi: 10.2174/156652406779010849
pubmed: 17168739
Jung SN, Yang WK, Kim J, Kim HS, Kim EJ, Yun H, Park H, Kim SS, Choe W, Kang I, Ha J (2008) Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 29(4):713–721. https://doi.org/10.1093/carcin/bgn032
doi: 10.1093/carcin/bgn032
pubmed: 18258605
Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW Jr, Cohen ML, Wang X, Siedlak SL, Dwyer BE, Hayashi T, Nakamura M, Nunomura A, Perry G (2010) Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19(1):363–372. https://doi.org/10.3233/JAD-2010-1239
doi: 10.3233/JAD-2010-1239
pubmed: 20061651
pmcid: 2842004
Zhang J, Xiang H, Liu J, Chen Y, He RR, Liu B (2020) Mitochondrial Sirtuin 3: new emerging biological function and therapeutic target. Theranostics 10(18):8315–8342. https://doi.org/10.7150/thno.45922
doi: 10.7150/thno.45922
pubmed: 32724473
pmcid: 7381741