Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) play major roles in peripheral clearance of amyloid-β (Aβ).
Objective:
To determine the relationship between baseline sLRP1/sRAGE and early cognitive decline in a longitudinal study and explore the possible effect of apolipoprotein E (APOE) on their association.
Methods:
Cognitively normal subjects were followed-up for 4 years. The baseline plasma levels of sLRP1 and sRAGE were measured using commercial ELISA kits. Global cognition was evaluated by Mini-Mental State Examination (MMSE), and cognitive decline was defined as a ≥2-point decrease of MMSE after 4 years. The association between baseline sLRP1/sRAGE and 4-year cognitive decline were analyzed using logistic regression analysis. Interaction analysis was performed to discover the potential effect of APOE genotype on the relationship.
Results:
769 participants were included in the final analysis, with 122 subjects (15.86%) were cognitive decline. Baseline sLRP1/sRAGE levels were not associated with 4-year cognitive decline after multivariable adjustments in the total cohort. However, there was significant interaction effect between sRAGE and APOE genotype on cognitive decline (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI]: 1.13–3.86, p = 0.019). Lower levels of sRAGE were associated with increased risk of cognitive decline among APOE ɛ4 non-carriers (adjusted OR = 1.60, 95% CI: 1.04–2.48, p = 0.034).
Conclusion:
Individuals with lower levels of sRAGE had an increased risk of 4-year cognitive decline in APOE ɛ4 non-carriers, indicating that the association between sRAGE and cognitive decline might depend on the APOE genotype. However, the specific mechanisms need to be further elucidated.
SelkoeDJ, HardyJ (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med8, 595–608.
2.
PanzaF, LozuponeM, SeripaD, ImbimboBP (2019) Amyloid-beta immunotherapy for Alzheimer disease: Is it now a long shot?Ann Neurol85, 303–315.
3.
HymanBT, PhelpsCH, BeachTG, BigioEH, CairnsNJ, CarrilloMC, DicksonDW, DuyckaertsC, FroschMP, MasliahE, MirraSS, NelsonPT, SchneiderJA, ThalDR, ThiesB, TrojanowskiJQ, VintersHV, MontineTJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement8, 1–13.
4.
QuinnKA, GrimsleyPG, DaiYP, TapnerM, ChestermanCN, OwensbyDA (1997) Soluble low density lipoprotein receptor-related protein (LRP) circulates in human plasma. J Biol Chem272, 23946–23951.
5.
ZhangL, BukulinM, KojroE, RothA, MetzVV, FahrenholzF, NawrothPP, BierhausA, PostinaR (2008) Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem283, 35507–35516.
6.
RaucciA, CugusiS, AntonelliA, BarabinoSM, MontiL, BierhausA, ReissK, SaftigP, BianchiME (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J22, 3716–3727.
Tarasoff-ConwayJM, CarareRO, OsorioRS, GlodzikL, ButlerT, FieremansE, AxelL, RusinekH, NicholsonC, ZlokovicBV, FrangioneB, BlennowK, MenardJ, ZetterbergH, WisniewskiT, de LeonMJ (2015) Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol11, 457–470.
9.
DeaneR, WuZ, ZlokovicBV (2004) RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke35, 2628–2631.
10.
YanSD, BierhausA, NawrothPP, SternDM (2009) RAGE and Alzheimer’s disease: A progression factor for amyloid-beta-induced cellular perturbation?J Alzheimers Dis16, 833.
11.
LiangF, JiaJ, WangS, QinW, LiuG (2013) Decreased plasma levels of soluble low density lipoprotein receptor-related protein-1 (sLRP) and the soluble form of the receptor for advanced glycation end products (sRAGE) in the clinical diagnosis of Alzheimer’s disease. J Clin Neurosci20, 357–361.
12.
EmanueleE, D’AngeloA, TomainoC, BinettiG, GhidoniR, PolitiP, BernardiL, MalettaR, BruniAC, GeroldiD (2005) Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Arch Neurol62, 1734–1736.
13.
LiK, DaiD, ZhaoB, YaoL, YaoS, WangB, YangZ (2010) Association between the RAGE G82S polymorphism and Alzheimer’s disease. J Neural Transm117, 97–104.
14.
XuXY, DengCQ, WangJ, DengXJ, XiaoQ, LiY, HeQ, FanWH, QuanFY, ZhuYP, ChengP, ChenGJ (2017) Plasma levels of soluble receptor for advanced glycation end products in Alzheimer’s disease. Int J Neurosci127, 454–458.
15.
GhidoniR, BenussiL, GlionnaM, FranzoniM, GeroldiD, EmanueleE, BinettiG (2008) Decreased plasma levels of soluble receptor for advanced glycation end products in mild cognitive impairment. J Neural Transm115, 1047–1050.
16.
SagareAP, DeaneR, ZetterbergH, WallinA, BlennowK, ZlokovicBV (2011) Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-beta is an early biomarker for mild cognitive impairment preceding Alzheimer’s disease. J Alzheimers Dis24, 25–34.
17.
HoltzmanDM (2001) Role of apoe/Abeta interactions in the pathogenesis of Alzheimer’s disease and cerebral amyloid angiopathy. J Mol Neurosci17, 147–155.
18.
GaoL, JiangY, WeiS, ShangS, LiP, ChenC, DangL, WangJ, HuoK, DengM, WangJ, ZhangR, QuQ (2018) The level of plasma amyloid-beta40 is correlated with peripheral transport proteins in cognitively normal adults: A population-based cross-sectional study. J Alzheimers Dis65, 951–961.
19.
WeiS, GaoL, JiangY, ShangSH, ChenC, DangLJ, ZhaoBY, ZhangJL, WangJ, HuoK, WangJY, ZhangR, QuQM (2020) Apolipoprotein E epsilon 4 allele is associated with plasma amyloid beta and amyloid beta transporter levels: A cross-sectional study in a rural area of Xi’an, China. Am J Geriatr Psychiatry28, 194–204.
20.
JiangY, ShangSH, LiP, ChenC, DangL, WangJJ, HuoK, DengMY, WangJY, QuQM (2018) Pulse pressure is associated with plasma amyloid-beta transport dysfunction. J Hypertens36, 569–579.
GaoL, WangJ, JiangY, WeiS, ShangS, ChenC, DangL, HuoK, DengM, WangJ, QuQ (2020) Relationship between peripheral transport proteins and plasma amyloid-beta in patients with Alzheimer’s disease were different from cognitively normal controls: A propensity score matching analysis. J Alzheimers Dis78, 699–709.
23.
WenhamPR, PriceWH, BlandellG (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet337, 1158–1159.
24.
SteinJ, LuppaM, MaierW, WagnerM, WolfsgruberS, SchererM, KöhlerM, EiseleM, WeyererS, WerleJ, BickelH, MöschE, WieseB, ProkeinJ, PentzekM, FuchsA, LeichtH, KönigHH, Riedel-HellerSG (2012) Assessing cognitive changes in the elderly: Reliable change indices for the Mini-Mental State Examination. Acta Psychiatr Scand126, 208–218.
25.
KopecekM, BezdicekO, SulcZ, LukavskyJ, StepankovaH (2017) Montreal Cognitive Assessment and Mini-Mental State Examination reliable change indices in healthy older adults. Int J Geriatr Psychiatry32, 868–875.
26.
HenselA, AngermeyerMC, Riedel-HellerSG (2007) Measuring cognitive change in older adults: Reliable change indices for the Mini-Mental State Examination. J Neurol Neurosurg Psychiatry78, 1298–1303.
27.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
28.
DrenthH, ZuidemaSU, KrijnenWP, BautmansI, van der SchansC, HobbelenH (2017) Association between advanced glycation end-products and functional performance in Alzheimer’s disease and mixed dementia. Int Psychogeriatr29, 1525–1534.
29.
JuranekJ, RayR, BanachM, RaiV (2015) Receptor for advanced glycation end-products in neurodegenerative diseases. Rev Neurosci26, 691–698.
30.
XieJ, MendezJD, Mendez-ValenzuelaV, Aguilar-HernandezMM (2013) Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell Signal25, 2185–2197.
31.
WalkerD, LueLF, PaulG, PatelA, SabbaghMN (2015) Receptor for advanced glycation endproduct modulators: A new therapeutic target in Alzheimer’s disease. Expert Opin Investig Drugs24, 393–399.
32.
MassaccesiL, GallieraE, GalimbertiD, FenoglioC, ArcaroM, GoiG, BarassiA, Corsi RomanelliMM (2019) Lag-time in Alzheimer’s disease patients: A potential plasmatic oxidative stress marker associated with ApoE4 isoform. Immun Ageing16, 7.
33.
UchidaT, ShirasawaM, WareLB, KojimaK, HataY, MakitaK, MednickG, MatthayZA, MatthayMA (2006) Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med173, 1008–1015.
34.
KalousovaM, HodkovaM, KazderovaM, FialovaJ, TesarV, Dusilova-SulkovaS, ZimaT (2006) Soluble receptor for advanced glycation end products in patients with decreased renal function. Am J Kidney Dis47, 406–411.
35.
Grauen LarsenH, YndigegnT, MarinkovicG, GrufmanH, MaresR, NilssonJ, GoncalvesI, SchiopuA (2019) The soluble receptor for advanced glycation end-products (sRAGE) has a dual phase-dependent association with residual cardiovascular risk after an acute coronary event. Atherosclerosis287, 16–23.
36.
NakamuraK, YamagishiSI, AdachiH, Kurita-NakamuraY, ImaizumiT (2006) Serum levels of sRAGE, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes. Mol Med13, 185–189.
37.
SaundersAM, StrittmatterWJ, SchmechelD, George-HyslopPH, Pericak-VanceMA, JooSH, RosiBL, GusellaJF, Crapper-MacLachlanDR, AlbertsMJ, et al. (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology43, 1467–1472.
38.
DeoP, DhillonVS, ChuaA, ThomasP, FenechM (2020) APOE epsilon4 carriers have a greater propensity to glycation and sRAGE which is further influenced by RAGE G82S polymorphism. J Gerontol A Biol Sci Med Sci75, 1899–1905.
39.
DhillonVS, DeoP, ChuaA, ThomasP, FenechM (2021) Sleep duration, Health Promotion Index (HPI), sRAGE and ApoE-ɛ4 genotype are associated with telomere length (TL) in healthy elderly Australians. J Gerontol A Biol Sci Med Sci, doi: 10.1093/gerona/glab264.
40.
MooldijkSS, ChenJ, IkramMA, ZillikensMC (2020) Letter to the Editor, Reacting to: “APOE ɛ4 Carriers Have a Greater Propensity to Glycation and sRAGE Which Is Further Influenced by RAGE G82S Polymorphism”. J Gerontol A Biol Sci Med Sci75, 1906–1907.
41.
DeaneR, Du YanS, SubmamaryanRK, LaRueB, JovanovicS, HoggE, WelchD, MannessL, LinC, YuJ, ZhuH, GhisoJ, FrangioneB, SternA, SchmidtAM, ArmstrongDL, ArnoldB, LiliensiekB, NawrothP, HofmanF, KindyM, SternD, ZlokovicB (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med9, 907–913.
