Affected albumin endocytosis as a new neurotoxicity mechanism of amyloid beta

Lourdes A. Vega Rasgado; Arantxa Tabernero Urbieta; José María Medina Jiménez; Lourdes A. Vega Rasgado; Arantxa Tabernero Urbieta; José María Medina Jiménez

doi:10.3934/Neuroscience.2020021

AIMS Neuroscience

2020, Volume 7, Issue 3: 344-359. doi: 10.3934/Neuroscience.2020021

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Research article

Affected albumin endocytosis as a new neurotoxicity mechanism of amyloid beta

1.
Laboratorio de Neuroquímica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, México
2.
Instituto de Neurociencias de Castilla y León (INCYL), c/Pintor Fernando Gallego 1, 37007 Salamanca, Spain

Received: 30 July 2020 Accepted: 17 September 2020 Published: 23 September 2020

Senile plaques, a hallmark of Alzheimer's disease, are composed by Amyloid-Beta (Aβ). Aβ 25-35 toxicity is caused mainly by increasing reactive oxygen species (ROS), which is reversed by albumin preventing Aβ internalization. In addition, key cellular processes and basic cell functions require of endocytosis, particularly relevant in neurons. To understand the protective effect of albumin and the toxicity mechanism of Aβ, the need of albumin uptake for neurons protection as well as the possible influence of Aβ on albumin endocytosis were investigated. With this aim the influence of lectin from soybeans (LEC), which prevents albumin endocytosis, on the effects of Aβ 25-35 on cellular morphology and viability, ROS generation and Aβ uptake with and without albumin in neurons in primary culture was investigated. Influence of Aβ on albumin endocytosis was studied using FITC-labelled albumin. LEC did not modify Aβ effects with or without albumin on neuronal morphology, but increased cell viability. LEC increased ROS generation with and without Aβ in the same magnitude. Diminished Aβ internalization observed with albumin was not affected by LEC. In presence of Aβ albumin is internalized, but endosomes did not deliver their cargo to the lysosomes for degradation. It is concluded that formation of Aβ-albumin complex does not require of albumin internalization, thus is extracellular. Aβ affects albumin endocytosis preventing late endosomes and lysosomes degradation, probably caused by changes in albumin structure or deregulation in vesicular transport. Considering the consequences such as its osmotic effects, the inability to exert its antioxidant properties, its effects on neuronal plasticity and excitability albumin affected endocytosis induced by Aβ is proposed as a new physiopathology mechanism in AD. It is hypothesized that there is critical intraneuronal level above which albumin becomes toxic.
- Alzheimer's disease,
- amyloid-β,
- albumin,
- endocytosis,
- neuronal dead
Citation: Lourdes A. Vega Rasgado, Arantxa Tabernero Urbieta, José María Medina Jiménez. Affected albumin endocytosis as a new neurotoxicity mechanism of amyloid beta[J]. AIMS Neuroscience, 2020, 7(3): 344-359. doi: 10.3934/Neuroscience.2020021

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Abstract

Senile plaques, a hallmark of Alzheimer's disease, are composed by Amyloid-Beta (Aβ). Aβ 25-35 toxicity is caused mainly by increasing reactive oxygen species (ROS), which is reversed by albumin preventing Aβ internalization. In addition, key cellular processes and basic cell functions require of endocytosis, particularly relevant in neurons. To understand the protective effect of albumin and the toxicity mechanism of Aβ, the need of albumin uptake for neurons protection as well as the possible influence of Aβ on albumin endocytosis were investigated. With this aim the influence of lectin from soybeans (LEC), which prevents albumin endocytosis, on the effects of Aβ 25-35 on cellular morphology and viability, ROS generation and Aβ uptake with and without albumin in neurons in primary culture was investigated. Influence of Aβ on albumin endocytosis was studied using FITC-labelled albumin. LEC did not modify Aβ effects with or without albumin on neuronal morphology, but increased cell viability. LEC increased ROS generation with and without Aβ in the same magnitude. Diminished Aβ internalization observed with albumin was not affected by LEC. In presence of Aβ albumin is internalized, but endosomes did not deliver their cargo to the lysosomes for degradation. It is concluded that formation of Aβ-albumin complex does not require of albumin internalization, thus is extracellular. Aβ affects albumin endocytosis preventing late endosomes and lysosomes degradation, probably caused by changes in albumin structure or deregulation in vesicular transport. Considering the consequences such as its osmotic effects, the inability to exert its antioxidant properties, its effects on neuronal plasticity and excitability albumin affected endocytosis induced by Aβ is proposed as a new physiopathology mechanism in AD. It is hypothesized that there is critical intraneuronal level above which albumin becomes toxic.

Abbreviation AD: Alzheimer disease; Aβ: Amyloid-Beta; ANOVA: Analysis of variance; BBB: Blood-brain barrier; BSA: Bovine serum albumin; CNS: Central nervous system; CSF: Cerebrospinal fluid; Cy3: Cyanine 3; DCF: 2′,7′-dichlorofluorescein; DCFH: 2′,7′-dichlorodihydrofluorescein; DCFH-DA: 2′,7′-dichlorodihydrofluorescein-diacetate; DMEM: Dulbeco's modified Eagle's medium; FCS: Fetal calf serum; FITC-BSA: Fluorescein isothiocyanate-albumin; GAP-43: Growth associated protein 43; MAP-2: Microtubules associated protein-2; LEC: Soybean lectin; MTT: 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide; ROS: Reactive oxygen species; SEM: Standard error of the mean;
Acknowledgments

This work was supported by the Junta de Castilla y León, Spain, and the Section of Postgraduate Studies and Research, Academic Secretary of National Polytechnic Institute, Mexico.

Conflict of interest

All authors declare no conflicts of interest in this paper.

References

[1]	Peterson BR (2008) Receptor-mediated endocytosis. The WileyEncyclopedia of Chemical Biology Hoboken, NJ: John Wiley and Sons Ltd, 1-13.
[2]	Schmidt MR, Haucke V (2007) Recycling endosomes in neuronal membrane traffic. Biol Cell 99: 333-342. doi: 10.1042/BC20070007
[3]	Benmerah A, Lamaze C (2007) Clathrin-coated pits: vive la difference? Traffic 8: 970-982. doi: 10.1111/j.1600-0854.2007.00585.x
[4]	Sandvig K, Torgersen ML, Raa HA, et al. (2008) Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity. Histochem Cell Biol 129: 267-276. doi: 10.1007/s00418-007-0376-5
[5]	Watson HA, Von Zastrow M, Wendland B (2004) Endocytosis. Encyclopedia of Molecular Cell Biology and Molecular Medicine Berlin, Germany: Wiley-VCH, 181-224.
[6]	Lentini D, Guzzi F, Pimpinelli F, et al. (2008) Polarization of caveolins and caveolae during migration of immortalized neurons. J Neurochem 104: 514-523.
[7]	Nixon RA (2005) Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging 26: 373-382. doi: 10.1016/j.neurobiolaging.2004.09.018
[8]	Behl C, Davis JB, Lesley R, et al. (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77: 817-827. doi: 10.1016/0092-8674(94)90131-7
[9]	Harris ME, Hensley K, Butterfield DA, et al. (1995) Direct evidence of oxidative injury produced by the Alzheimer's beta-amyloid peptide (1–40) in cultured hippocampal neurons. Exp Neurol 131: 193-202. doi: 10.1016/0014-4886(95)90041-1
[10]	Bergin DH, Liu P (2010) Agmatine protects against beta-amyloid 25-35-induced memory impairments in the rat. Neuroscience 169: 794-811. doi: 10.1016/j.neuroscience.2010.05.004
[11]	Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, et al. (1995) Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem 64: 253-265. doi: 10.1046/j.1471-4159.1995.64010253.x
[12]	Varadarajan S, Kanski J, Aksenova M, et al. (2001) Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's A beta (1–42) and A beta (25−35). J Am Chem Soc 123: 5625-5631. doi: 10.1021/ja010452r
[13]	Koudinov AR, Berezov TT (2004) Alzheimer's amyloid-beta (A beta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiol Exp (Wars) 64: 71-79.
[14]	Malyshev IY, Wiegant FA, Mashina SY, et al. (2005) Possible use of adaptation to hypoxia in Alzheimer's disease: a hypothesis. Med Sci Monit 11: HY31-HY38.
[15]	Fishman PS, Farrand DA, Kristt DA (1990) Internalization of plasma proteins by cerebellar Purkinje cells. J Neurol Sci 100: 43-49. doi: 10.1016/0022-510X(90)90011-B
[16]	Granda B, Tabernero A, Tello V, et al. (2003) Oleic acid induces GAP-43 expression through a protein kinase C-mediated mechanism that is independent of NGF but synergistic with NT-3 and NT-4/5. Brain Res 988: 1-8. doi: 10.1016/S0006-8993(03)03253-0
[17]	Juurlink BH, Devon RM (1990) Macromolecular translocation—a possible function of astrocytes. Brain Res 533: 73-77. doi: 10.1016/0006-8993(90)91797-K
[18]	Tabernero A, Medina A, Sanchez-Abarca LI, et al. (1999) The effect of albumin on astrocyte energy metabolism is not brought about through the control of cytosolic Ca²⁺ concentrations but by free-fatty acid sequestration. Glia 25: 1-9. doi: 10.1002/(SICI)1098-1136(19990101)25:1<1::AID-GLIA1>3.0.CO;2-2
[19]	Vicario C, Medina JM (1992) Metabolism of lactate in the rat brain during the early neonatal period. J Neurochem 59: 32-40. doi: 10.1111/j.1471-4159.1992.tb08872.x
[20]	Tildon JT, McKenna MC, Stevenson J, et al. (1993) Transport of L-lactate by cultured rat brain astrocytes. Neurochem Res 18: 177-184. doi: 10.1007/BF01474682
[21]	Tabernero A, Granda B, Medina A, et al. (2002) Albumin promotes neuronal survival by increasing the synthesis and release of glutamate. J Neurochem 81: 881-891. doi: 10.1046/j.1471-4159.2002.00843.x
[22]	Puzzo D, Privitera L, Leznik E, et al. (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28: 14537-14545. doi: 10.1523/JNEUROSCI.2692-08.2008
[23]	Garcia-Osta A, Alberini CM (2009) Amyloid beta mediates memory formation. Learn Mem 16: 267-272. doi: 10.1101/lm.1310209
[24]	Morley JE, Farr SA, Banks WA, et al. (2010) A physiological role for amyloid-beta protein:enhancement of learning and memory. J Alzheimers Dis 19: 441-449. doi: 10.3233/JAD-2010-1230
[25]	Masters CL, Selkoe DJ (2012) Biochemistry of amyloid beta-protein and amyloid deposits in Alzheimer disease. Cold Spring Harbor Perspect Med 2: a006262. doi: 10.1101/cshperspect.a006262
[26]	Stevens RW, Elmendorf D, Gourlay M, et al. (1979) Application of fluoroimmunoassay to cerebrospinal fluid immunoglobulin G and albumin. J Clin Microbiol 10: 346-350. doi: 10.1128/JCM.10.3.346-350.1979
[27]	Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harbor Perspect Biol 7: a020412. doi: 10.1101/cshperspect.a020412
[28]	Daneman R (2012) The blood-brain barrier in health and disease. Ann Neurol 72: 648-672. doi: 10.1002/ana.23648
[29]	Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57: 178-201. doi: 10.1016/j.neuron.2008.01.003
[30]	Erickson MA, Banks WA (2013) Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. J Cereb Blood Flow Metab 33: 1500-1513. doi: 10.1038/jcbfm.2013.135
[31]	Zenaro E, Piacentino G, Constantin G (2017) The blood-brain barrier in Alzheimer's disease. Neurobiol Dis 107: 41-56. doi: 10.1016/j.nbd.2016.07.007
[32]	Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 28: 202-208. doi: 10.1016/j.tins.2005.02.001
[33]	Bowman GL, Kaye JA, Moore M, et al. (2007) Blood-brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology 68: 1809-1814. doi: 10.1212/01.wnl.0000262031.18018.1a
[34]	Vega L, Arroyo AA, Tabernero A, et al. (2009) Albumin-blunted deleterious effect of amyloid-beta by preventing the internalization of the peptide into neurons. J Alzheimers Dis 17: 795-805. doi: 10.3233/JAD-2009-1093
[35]	Shearman MS, Ragan CI, Iversen LL (1994) Inhibition of PC12 cell redox activity is a specific, early indicator of the mechanism of beta-amyloid-mediated cell death. Proc Natl Acad Sci USA 91: 1470-1474. doi: 10.1073/pnas.91.4.1470
[36]	Megias L, Guerri C, Fornas E, et al. (2000) Endocytosis and transcytosis in growing astrocytes in primary culture. Possible implications in neural development. Int J Dev Biol 44: 209-221.
[37]	Murk JL, Humbel BM, Ziese U, et al. (2003) Endosomal compartmentalization in three dimensions: implications for membrane fusion. Proc Natl Acad Sci USA 100: 13332-13337. doi: 10.1073/pnas.2232379100
[38]	Tabernero A, Bolanos JP, Medina JM (1993) Lipogenesis from lactate in rat neurons and astrocytes in primary culture. Biochem J 294: 635-638. doi: 10.1042/bj2940635
[39]	Denizot F, Lang R (1986) Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 89: 271-277. doi: 10.1016/0022-1759(86)90368-6
[40]	Rosenkranz AR, Schmaldienst S, Stuhlmeier KM, et al. (1992) A microplate assay for the detection of oxidative products using 2′,7′-dichlorofluorescin-diacetate. J Immunol Methods 156: 39-45. doi: 10.1016/0022-1759(92)90008-H
[41]	Tabernero A, Lavado EM, Granda B, et al. (2001) Neuronal differentiation is triggered by oleic acid synthesized and released by astrocytes. J Neurochem 79: 606-616. doi: 10.1046/j.1471-4159.2001.00598.x
[42]	Lis H, Sela BA, Sachs L, et al. (1970) Specific inhibition by N-acetyl-D-galactosamine of the interaction between soybean agglutinin and animal cell surfaces. Biochim Biophys Acta 211: 582-585. doi: 10.1016/0005-2736(70)90265-8
[43]	Tabernero A, Velasco A, Granda B, et al. (2002) Transcytosis of albumin in astrocytes activates the sterol regulatory element-binding protein-1, which promotes the synthesis of the neurotrophic factor oleic acid. J Biol Chem 277: 4240-4246. doi: 10.1074/jbc.M108760200
[44]	Schnitzer JE, Carley WW, Palade GE (1988) Albumin interacts specifically with a 60-kDa microvascular endothelial glycoprotein. Proc Natl Acad Sci USA 85: 6773-6777. doi: 10.1073/pnas.85.18.6773
[45]	Crescenzi O, Tomaselli S, Guerrini R, et al. (2002) Solution structure of the Alzheimer amyloid beta-peptide (1–42) in an apolar microenvironment. Similarity with a virus fusion domain. Eur J Biochem 269: 5642-5648. doi: 10.1046/j.1432-1033.2002.03271.x
[46]	D'Ursi AM, Armenante MR, Guerrini R, et al. (2004) Solution structure of amyloid beta-peptide (25–35) in different media. J Med Chem 47: 4231-4238. doi: 10.1021/jm040773o
[47]	Chen GF, Xu TH, Yan Y, et al. (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38: 1205-1235. doi: 10.1038/aps.2017.28
[48]	Kaminsky YG, Marlatt MW, Smith MA, et al. (2010) Subcellular and metabolic examination of amyloid-beta peptides in Alzheimer disease pathogenesis: evidence for Abeta (25–35). Exp Neurol 221: 26-37. doi: 10.1016/j.expneurol.2009.09.005
[49]	Pena F, Ordaz B, Balleza-Tapia H, et al. (2010) Beta-amyloid protein (25–35) disrupts hippocampal network activity: role of Fyn-kinase. Hippocampus 20: 78-96.
[50]	Bi H, Sze CI (2002) N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer's disease. J Neurol Sci 200: 11-18. doi: 10.1016/S0022-510X(02)00087-4
[51]	Wesen E, Jeffries GDM, Matson Dzebo M, et al. (2017) Endocytic uptake of monomeric amyloid-beta peptides is clathrin- and dynamin-independent and results in selective accumulation of Abeta (1–42) compared to Abeta (1–40). Sci Rep 7: 2021. doi: 10.1038/s41598-017-02227-9
[52]	Glick JL (1991) Proposed mechanism for alteration of albumin structure and function in Alzheimer's disease. J Theor Biol 148: 283-286. doi: 10.1016/S0022-5193(05)80346-7
[53]	Liu Z, Liu J, Wang S, et al. (2016) Neuronal uptake of serum albumin is associated with neuron damage during the development of epilepsy. Exp Ther Med 12: 695-701. doi: 10.3892/etm.2016.3397
[54]	Hassel B, Iversen EG, Fonnum F (1994) Neurotoxicity of albumin in vivo. Neurosci Lett 167: 29-32. doi: 10.1016/0304-3940(94)91020-0
[55]	LeVine SM (2016) Albumin and multiple sclerosis. BMC Neurol 16: 47. doi: 10.1186/s12883-016-0564-9
[56]	Basi GS, Jacobson RD, Virag I, et al. (1987) Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth. Cell 49: 785-791. doi: 10.1016/0092-8674(87)90616-7
[57]	Gorgels TG, Van Lookeren Campagne M, Oestreicher AB, et al. (1989) B-50/GAP43 is localized at the cytoplasmic side of the plasma membrane in developing and adult rat pyramidal tract. J Neurosci 9: 3861-3869. doi: 10.1523/JNEUROSCI.09-11-03861.1989
[58]	Huang SL, Merat D, Cheung WY (1989) Phosphatidylinositol modulates the response of calmodulin-dependent phosphatase to calmodulin. Arch Biochem Biophys 270: 42-49. doi: 10.1016/0003-9861(89)90005-2
[59]	James G, Olson EN (1989) Identification of a novel fatty acylated protein that partitions between the plasma membrane and cytosol and is deacylated in response to serum and growth factor stimulation. J Biol Chem 264: 20998-21006.
[60]	Jochen A, Hays J, Lianos E, et al. (1991) Insulin stimulates fatty acid acylation of adipocyte proteins. Biochem Biophys Res Commun 177: 797-801. doi: 10.1016/0006-291X(91)91859-B
[61]	Patterson SI, Skene JH (1999) A shift in protein S-palmitoylation, with persistence of growth-associated substrates, marks a critical period for synaptic plasticity in developing brain. J Neurobiol 39: 423-437. doi: 10.1002/(SICI)1097-4695(19990605)39:3<423::AID-NEU8>3.0.CO;2-Z
[62]	Rossi S, Furlan R, De Chiara V, et al. (2012) Interleukin-1 beta causes synaptic hyperexcitability in multiple sclerosis. Ann Neurol 71: 76-83. doi: 10.1002/ana.22512
[63]	Li V, Brustovetsky T, Brustovetsky N (2009) Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death. Exp Neurol 218: 171-182. doi: 10.1016/j.expneurol.2009.02.007
[64]	Paul J, Strickland S, Melchor JP (2007) Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. J Exp Med 204: 1999-2008. doi: 10.1084/jem.20070304
[65]	Revett TJ, Baker GB, Jhamandas J, et al. (2013) Glutamate system, amyloid ss peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. J Psychiatry Neurosci 38: 6-23. doi: 10.1503/jpn.110190
[66]	Malik AR, Willnow TE (2019) Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. Int J Mol Sci 20: 5671. doi: 10.3390/ijms20225671

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