Aging Alters MRNA Expression of Amyloid Transporter Genes at the Blood-brain Barrier

Overview

Journal Neurobiol Aging

Publisher Elsevier

Specialties Geriatrics
Neurology
Physiology

Date 2017 Jun 28

PMID 28654861

Citations 28

Authors

Doreen Osgood

Miles C Miller

Arthur A Messier

Liliana Gonzalez

Gerald D Silverberg

Affiliations

Soon will be listed here.

Abstract

Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Aβ) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Aβ accumulation.

Citing Articles

Lipidopathy disrupts peripheral and central amyloid clearance in Alzheimer's disease: Where are our knowledge.

Darabi S, Charkhat Gorgich E, Moradi F, Rustamzadeh A IBRO Neurosci Rep. 2025; 18:191-199.

PMID: 39906286 PMC: 11791331. DOI: 10.1016/j.ibneur.2025.01.004.

The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer's Disease Etiopathology.

Fanlo-Ucar H, Picon-Pages P, Herrera-Fernandez V, Ill-Raga G, Munoz F Antioxidants (Basel). 2024; 13(10).

PMID: 39456461 PMC: 11505517. DOI: 10.3390/antiox13101208.

Effects silymarin and rosuvastatin on amyloid-carriers level in dyslipidemic Alzheimer's patients: A double-blind placebo-controlled randomized clinical trial.

Rustamzadeh A, Sadigh N, Vahabi Z, Khamseh F, Mohebi N, Ghobadi Z IBRO Neurosci Rep. 2024; 17:108-121.

PMID: 39139290 PMC: 11321388. DOI: 10.1016/j.ibneur.2024.07.002.

Cerebral amyloid angiopathy and the immune system.

Munsterman D, Falcione S, Long R, Boghozian R, Joy T, Camicioli R Alzheimers Dement. 2024; 20(7):4999-5008.

PMID: 38881491 PMC: 11247707. DOI: 10.1002/alz.13826.

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems.

Loeffler D J Alzheimers Dis. 2024; 100(2):379-411.

PMID: 38875041 PMC: 11307100. DOI: 10.3233/JAD-240212.

References

Zlokovic B, Begley D . Blood-brain barrier permeability to leucine-enkephalin, D-alanine2-D-leucine5-enkephalin and their N-terminal amino acid (tyrosine). Brain Res. 1985; 336(1):125-32. DOI: 10.1016/0006-8993(85)90423-8. View

Attems J, Jellinger K . Neuropathological correlates of cerebral multimorbidity. Curr Alzheimer Res. 2013; 10(6):569-77. DOI: 10.2174/15672050113109990002. View

Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Ukitsu M, Genda Y . Decrease with age in methylcytosines in the promoter region of receptor for advanced glycated end products (RAGE) gene in autopsy human cortex. Brain Res Mol Brain Res. 1999; 65(1):124-8. DOI: 10.1016/s0169-328x(98)00351-9. View

Bell R, Deane R, Chow N, Long X, Sagare A, Singh I . SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol. 2008; 11(2):143-53. PMC: 2654279. DOI: 10.1038/ncb1819. View

KUTT H, Herz J, Stanley K . Structure of the low-density lipoprotein receptor-related protein (LRP) promoter. Biochim Biophys Acta. 1989; 1009(3):229-36. DOI: 10.1016/0167-4781(89)90107-3. View

Glaser C, Schulz S, Handschug K, Huse K, Birkenmeier G . Genetic and functional characteristics of the human in vivo LRP1/A2MR receptor suggested as a risk marker for Alzheimer's disease and other complex (degenerative) diseases. Neurosci Res. 2004; 50(1):85-101. DOI: 10.1016/j.neures.2004.06.001. View

Schmidt A, Hasu M, Popov D, Zhang J, Chen J, Yan S . Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins. Proc Natl Acad Sci U S A. 1994; 91(19):8807-11. PMC: 44695. DOI: 10.1073/pnas.91.19.8807. View

Church R, Miller M, Freestone D, Chiu C, Osgood D, Machan J . Amyloid-beta accumulation, neurogenesis, behavior, and the age of rats. Behav Neurosci. 2014; 128(4):523-36. DOI: 10.1037/a0036433. View

Li J, Schmidt A . Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem. 1997; 272(26):16498-506. DOI: 10.1074/jbc.272.26.16498. View

10.

Hong H, Liu L, Liao J, Wang T, Ye F, Wu J . Downregulation of LRP1 [correction of LPR1] at the blood-brain barrier in streptozotocin-induced diabetic mice. Neuropharmacology. 2009; 56(6-7):1054-9. DOI: 10.1016/j.neuropharm.2009.03.001. View

11.

Castellano J, Aledo R, Sendra J, Costales P, Juan-Babot O, Badimon L . Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2011; 31(6):1411-20. DOI: 10.1161/ATVBAHA.111.225490. View

12.

Daneman R, Zhou L, Agalliu D, Cahoy J, Kaushal A, Barres B . The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One. 2010; 5(10):e13741. PMC: 2966423. DOI: 10.1371/journal.pone.0013741. View

13.

Cirrito J, Deane R, Fagan A, Spinner M, Parsadanian M, Finn M . P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005; 115(11):3285-90. PMC: 1257538. DOI: 10.1172/JCI25247. View

14.

Kang D, Pietrzik C, Baum L, Chevallier N, Merriam D, Kounnas M . Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest. 2000; 106(9):1159-66. PMC: 301422. DOI: 10.1172/JCI11013. View

15.

Echavarri C, Burgmans S, Caballero M, Garcia-Bragado F, Verhey F, Uylings H . Co-occurrence of different pathologies in dementia: implications for dementia diagnosis. J Alzheimers Dis. 2012; 30(4):909-17. DOI: 10.3233/JAD-2012-111400. View

16.

Christensen B, Houseman E, Marsit C, Zheng S, Wrensch M, Wiemels J . Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 2009; 5(8):e1000602. PMC: 2718614. DOI: 10.1371/journal.pgen.1000602. View

17.

Donahue J, Flaherty S, Johanson C, Duncan 3rd J, Silverberg G, Miller M . RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. Acta Neuropathol. 2006; 112(4):405-15. DOI: 10.1007/s00401-006-0115-3. View

18.

Liu Q, Zerbinatti C, Zhang J, Hoe H, Wang B, Cole S . Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron. 2007; 56(1):66-78. PMC: 2045076. DOI: 10.1016/j.neuron.2007.08.008. View

19.

Pilorget A, Demeule M, Barakat S, Marvaldi J, Luis J, Beliveau R . Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J Neurochem. 2007; 100(5):1203-10. DOI: 10.1111/j.1471-4159.2006.04295.x. View

20.

Carrano A, Snkhchyan H, Kooij G, van der Pol S, van Horssen J, Veerhuis R . ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy. Neurobiol Aging. 2013; 35(3):565-75. DOI: 10.1016/j.neurobiolaging.2013.09.015. View