Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aβ oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aβ1–42 or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aβ accumulation. Furthermore, adult male rats received Aβ1–42 or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aβ1–42 and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aβ administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aβ oligomers in the cortex and CA1 only. Our findings indicate that Aβ1–42 and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy.
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21 March 2024
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s10571-024-01468-3
References
Ahmed Z, Cooper J, Murray TK et al (2014) A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 127:667–683. https://doi.org/10.1007/s00401-014-1254-6
Amorini AM, Lazzarino G, Di Pietro V et al (2016) Metabolic, enzymatic and gene involvement in cerebral glucose dysmetabolism after traumatic brain injury. Biochim Biophys Acta 1862:679–687. https://doi.org/10.1016/j.bbadis.2016.01.023
Ansari MA, Abdul HM, Joshi G et al (2009) Protective effect of quercetin in primary neurons against Aβ (1–42): relevance to Alzheimer's disease. J Nutr Biochem 20:269–275. https://doi.org/10.1016/j.jnutbio.2008.03.002
Boyd-Kimball D, Sultana R, Poon HF et al (2005) Proteomic identification of proteins specifically oxidized by intracerebral injection of amyloid β-peptide (1–42) into rat brain: implications for Alzheimer’s disease. Neuroscience 132:313–324. https://doi.org/10.1016/j.neuroscience.2004.12.022
Brier MR, Gordon B, Friedrichsen K et al (2016) Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 8:338ra66–338ra66. https://doi.org/10.1126/scitranslmed.aaf2362
Caruso A, Nicoletti F, Mango D et al (2018) Stress as risk factor for Alzheimer’s disease. Pharmacol Res 132:130–134. https://doi.org/10.1016/j.phrs.2018.04.017
Castillo-Carranza DL, Guerrero-Muñoz MJ, Sengupta U et al (2015) Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model. J Neurosci 35:4857–4868. https://doi.org/10.1523/JNEUROSCI.4989-14.2015
Chabrier MA, Blurton-Jones M, Agazaryan AA et al (2012) Soluble Aβ promotes wild-type tau pathology in vivo. J Neurosci 32:17345–17350. https://doi.org/10.1523/JNEUROSCI.0172-12.2012
Chavez JC, Baranova O, Lin J et al (2006) The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci 26:9471–9481. https://doi.org/10.1523/JNEUROSCI.2838-06.2006
Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909. https://doi.org/10.1038/ncb1901
Congdon EE, Sigurdsson EM (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14(7):399–415. https://doi.org/10.1038/s41582-018-0013-z
Dai CL, Hu W, Tung YC, Liu F, Gong CX, Iqbal K (2018) Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3× Tg-AD mice. Alzheimers Res Ther 10(1):13. https://doi.org/10.1186/s13195-018-0341-7
De Felice FG, Wu D, Lambert MP et al (2008) Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers. Neurobiol Aging 29:1334–1347. https://doi.org/10.1016/j.neurobiolaging.2007.02.029
Di Domenico F, Pupo G, Giraldo E et al (2016) Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients. Free Radic Biol Med 91:1–9. https://doi.org/10.1016/j.freeradbiomed.2015.12.004
Di Pietro V, Lazzarino G, Amorini AM et al (2014) Neuroglobin expression and oxidant/antioxidant balance after graded traumatic brain injury in the rat. Free Radic Biol Med 69:258–264. https://doi.org/10.1016/j.freeradbiomed.2014.01.032
Donovan NJ, Locascio JJ, Marshall GA et al (2018) Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults. Am J Psychiatry 175:530–537. https://doi.org/10.1176/appi.ajp.2017.17040442
Egan MF, Kost J, Voss T et al (2019) Randomized trial of verubecestat for prodromal alzheimer’s disease. N Engl J Med 380:1408–1420. https://doi.org/10.1056/NEJMoa1812840
El Halawany AM, Sayed NSE, Abdallah HM et al (2017) Protective effects of gingerol on streptozotocin-induced sporadic Alzheimer’s disease: emphasis on inhibition of β-amyloid, COX-2, alpha-, beta-secretases and APH1a. Sci Rep 7:2902. https://doi.org/10.1038/s41598-017-02961-0
Ferrer I, García MA, Carmona M et al (2019) Involvement of oligodendrocytes in tau seeding and spreading in tauopathies. Front Aging Neurosci 11:112. https://doi.org/10.3389/fnagi.2019.00112
Fitzpatrick AW, Falcon B, He S et al (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185. https://doi.org/10.1038/nature23002
Floyd RA, Hensley K (2002) Oxidative stress in brain aging: implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 23:795–807. https://doi.org/10.1016/s0197-4580(02)00019-2
Gabryelewicz T, Styczynska M, Pfeffer A et al (2004) Prevalence of major and minor depression in elderly persons with mild cognitive impairment—MADRS factor analysis. Int J Geriatr Psychiatry 19:1168–1172. https://doi.org/10.1002/gps.1235
Galeano P, Martino Adami PV, Do Carmo S et al (2014) Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease. Front Neurosci 8:321. https://doi.org/10.3389/fnbeh.2014.00321
Gibb GM, Pearce J, Betts JC, Lovestone S, Hoffmann MM, Maerz W, Blackstock WP, Anderton BH (2000) Differential effects of apolipoprotein E isoforms on phosphorylation at specific sites on tau by glycogen synthase kinase-3β identified by nano-electrospray mass spectrometry. FEBS Lett 485(2–3):99–103. https://doi.org/10.1016/s0014-5793(00)02196-7
Gibbs E, Silverman JM, Zhao B et al (2019) A rationally designed humanized antibody selective for amyloid beta oligomers in Alzheimer’s disease. Sci Rep 9:9870. https://doi.org/10.1038/s41598-019-46306-5
Gomes LA, Hipp SA, Upadhaya AR et al (2019) Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Acta Neuropathol 138:913–941. https://doi.org/10.1007/s00401-019-02053-5
Gu X, Sun J, Li S et al (2013) Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Aβ production. Oxid Med Cell Longev 34:1069–1079. https://doi.org/10.1155/2015/604658
Guglielmotto M, Giliberto L, Tamagno E et al (2010) Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors. Front Aging Neurosci 2:3. https://doi.org/10.3389/neuro.24.003.2010
Guo JL, Lee VMY (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20:130. https://doi.org/10.1038/nm.3457
Guo X, Wu X, Ren L et al (2011) Epigenetic mechanisms of amyloid-β production in anisomycin-treated SH-SY5Y cells. Neuroscience 194:272–281. https://doi.org/10.1016/j.neuroscience.2011.07.012
Hajipour MJ, Santoso MR, Rezaee F et al (2017) Advances in alzheimer’s diagnosis and therapy: the implications of nanotechnology. Trends Biotechnol 35:937–953. https://doi.org/10.1016/j.tibtech.2017.06.002
Halliwell B, Gutteridge JM (2015) Free radicals in biology and medicine. Oxford University Press, Oxford
He Z, Guo JL, McBride JD et al (2018) Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24:29. https://doi.org/10.1038/nm.4443
Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M (2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378(4):321–330. https://doi.org/10.1056/NEJMoa1705971
Hooshmandi E, Ghasemi R, Iloun P et al (2019) The neuroprotective effect of agmatine against amyloid β-induced apoptosis in primary cultured hippocampal cells involving ERK, Akt/GSK-3β, and TNF-α. Mol Biol Rep 46:489–496. https://doi.org/10.1007/s11033-018-4501-4
Jack CR Jr, Knopman DS, Jagust WJ et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 9:119–128. https://doi.org/10.1016/S1474-4422(09)70299-6
Jarosz-Griffiths HH, Noble E, Rushworth JV et al (2016) Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem 291:3174–3183. https://doi.org/10.1074/jbc.R115.702704
Jessen FJNRN (2019) Refining the understanding of typical Alzheimer disease. Nat Rev Neurol 15:623–624. https://doi.org/10.1038/s41582-019-0259-0
Kondo A, Shahpasand K, Mannix R et al (2015) Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523:431. https://doi.org/10.1038/nature14658
Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U et al (2012) Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep 2:700. https://doi.org/10.1038/srep00700
Liu P-P, **e Y, Meng X-Y et al (2019) History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Target Ther 4:1–22. https://doi.org/10.1038/s41392-019-0063-8
Lue L-F, Kuo Y-M, Roher AE et al (1999) Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155:853–862. https://doi.org/10.1016/s0002-9440(10)65184-x
Ma Q-L, Yang F, Rosario ER et al (2009) β-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 29:9078–9089. https://doi.org/10.1523/JNEUROSCI.1071-09.2009
Mairet-Coello G, Courchet J, Pieraut S et al (2013) The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron 78:94–108. https://doi.org/10.1016/j.neuron.2013.02.003
Mudher A, Colin M, Dujardin S et al (2017) What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun 5:99. https://doi.org/10.1186/s40478-017-0488-7
Mufson EJ, Ward S, Binder L (2014) Prefibrillar tau oligomers in mild cognitive impairment and Alzheimer's disease. Neurodegener Dis 13(2–3):151–153. https://doi.org/10.1159/000353687
Nakamura K, Greenwood A, Binder L et al (2012) Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell 149:232–244. https://doi.org/10.1016/j.cell.2012.02.016
Naserkhaki R, Zamanzadeh S, Baharvand H et al (2019) cis pT231-tau drives neurodegeneration in bipolar disorder. ACS Chem Neurosci 10:1214–1221. https://doi.org/10.1021/acschemneuro.8b00629
Nelson PT, Braak H, Markesbery WR et al (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14. https://doi.org/10.1097/NEN.0b013e3181919a48
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates in stereotaxic coordinates. Elsevier, Amsterdam
Pei-Pei L, Yi X, **ao-Yan M, Jian-Sheng K (2019) History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Target Ther 4(1):1–22. https://doi.org/10.1038/s41392-019-0063-8
Pentkowski NS, Berkowitz LE, Thompson SM et al (2018) Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease. Neurobiol Aging 61:169–176. https://doi.org/10.1016/j.neurobiolaging.2017.09.024
Petrasek T, Vojtechova I, Lobellova V, Popelikova A, Janikova M, Brozka H, Houdek P, Sladek M, Sumova A, Kristofikova Z, Vales K (2018) The McGill transgenic rat model of Alzheimer's disease displays cognitive and motor impairments, changes in anxiety and social behavior, and altered circadian activity. Front Aging Neurosci 10:250. https://doi.org/10.3389/fnagi.2018.00250
Phiel CJ, Wilson CA, Lee VMY, Klein PS (2003) GSK-3α regulates production of Alzheimer's disease amyloid-β peptides. Nature 423(6938):435–439. https://doi.org/10.1038/nature01640
Quon D, Wang Y, Catalano R et al (1991) Formation of β-amyloid protein deposits in brains of transgenic mice. Nature 352:239. https://doi.org/10.1038/352239a0
Selkoe DJ (2011) Resolving controversies on the path to Alzheimer's therapeutics. Nat Med 17:1060. https://doi.org/10.1038/nm.2460
Selkoe DJ (2012) Preventing Alzheimer’s disease. Science 337:1488–1492. https://doi.org/10.1126/science.1228541
Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480. https://doi.org/10.1152/jappl.2000.88.4.1474
Shahpasand K, Uemura I, Saito T et al (2012) Regulation of mitochondrial transport and inter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer's disease. J Neurosci 32:2430–2441. https://doi.org/10.1523/JNEUROSCI.5927-11.2012
Tackenberg C, Grinschgl S, Trutzel A et al (2013) NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss. Cell Death Dis 4:e608. https://doi.org/10.1038/cddis.2013.129
Tackenberg C, Nitsch RM (2019) The secreted APP ectodomain sAPPα, but not sAPPβ, protects neurons against Aβ oligomer-induced dendritic spine loss and increased tau phosphorylation. Mol Brain 12:27. https://doi.org/10.1186/s13041-019-0447-2
Taki-Nakano N, Ohzeki H, Kotera J et al (2014) Cytoprotective effects of 12-oxo phytodienoic acid, a plant-derived oxylipin jasmonate, on oxidative stress-induced toxicity in human neuroblastoma SH-SY5Y cells. Biochim Biophys Acta 1840:3413–3422. https://doi.org/10.1016/j.bbagen.2014.09.003
Viola KL, Klein WL (2015) Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 129(2):183–206. https://doi.org/10.1007/s00401-015-1386-3
Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848. https://doi.org/10.1038/nprot.2006.116
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322. https://doi.org/10.1038/nprot.2007.44
Wei Y, Zhou J, Wu J et al (2019) ERβ promotes Aβ degradation via the modulation of autophagy. Cell Death Dis 10:565. https://doi.org/10.1038/s41419-019-1786-8
Zamani E, Parviz M, Roghani M et al (2019) Key mechanisms underlying netrin-1 prevention of impaired spatial and object memory in Aβ1–42 CA1-injected rats. Clin Exp Pharmacol Physiol 46:86–93. https://doi.org/10.1111/1440-1681.13020
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The study was supported by funding from the Iran University of Medical Sciences and Health Services (Grant # 443) and a Grant # 97000115 from Royan Institute.
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MP, MJ and KS: designed the methods, conducted the experiments, analyzed the data, and wrote the paper; SM, RA, SMN, HP, NF, SMH: analyzed the data, performed the experiments, and wrote the paper. The manuscript was revised and approved by all authors.
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Supplementary file1 (TIF 537 kb)—Supplemental Fig. 1The expression of HIF1-α in the primary neuronal cells was assessed by immunoblotting, 24 hoursafter the administration of 200 μM H2O2.
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Supplementary file2 (TIF 740 kb)—Supplemental Fig. 2TBI leads to the robust induction of pathogenic species of p-tau in the frontal cortex after 72 hours.The rat was subjected to TBI by a 450 g weight drop from 2 m heights and followed byimmunofluorescence (cis, red; DNA, blue) (a) and immunoblotting (b). Arrows indicate positivecis P-tau cells.
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Supplementary file3 (TIF 10484 kb)—Supplemental Fig. 3 cis P-tau showed more severe distribution than Aβ at two and eight weeks post-microinjection.Western blot analysis revealed the spreading of cis P-tau in the CA1 (a), cortex (b), corpuscallosum (c), and striatum (d) of Aβ-injected animals. Aβ showed limited spread in CA1 (a) andcortex (b). The densitometry values as a ratio to β-actin were normalized to control group (***P< 0.001 and **P< 0.01, and *p < 0.05 vs. control group, One-way ANOVA test). Data arerepresented as the mean ± SEM. (n = 3). Cont, control; Veh, vehicle; Aβ-Inj, Aβ-Injected; P-tau-Inj, P-tau-Injected.
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Supplementary file4 (TIF 1551 kb)—Supplemental Fig. 4Immunofluorescence staining for the time-dependent progression of AT8 during two and eightweeks post-microinjection. Representative images are sections of the cortex and CA1 at two (a)and eight (b) weeks after the microinjection (40X field, Aβ oligomers (green); DAPI (blue)).Arrows indicate AT8 marker. Quantification of the immunofluorescence data shows a significantincrease in the development of AT8 in the CA1 and cortex in the treated groups than control group(***P < 0.001, One-way ANOVA). Values are expressed as the mean ± SEM.
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Supplementary file5 (TIF 1672 kb)—Supplemental Fig. 5Immunofluorescence staining for time-dependent progression of AT100 during two and eightweeks post-microinjection. Representative images are sections of the cortex and CA1 at two (a)and eight (b) weeks after the microinjection (40X field, Aβ oligomers (green); DAPI (blue)).Arrows indicate AT100 marker. Quantification of the immunofluorescence data shows asignificant increase in the development of AT100 in the CA1 and cortex in the treated groups thancontrol group. (***P < 0.001, One-way ANOVA). Values are expressed as the mean ± SEM.
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Pourhamzeh, M., Joghataei, M.T., Mehrabi, S. et al. RETRACTED ARTICLE: The Interplay of Tau Protein and β-Amyloid: While Tauopathy Spreads More Profoundly Than Amyloidopathy, Both Processes Are Almost Equally Pathogenic. Cell Mol Neurobiol 41, 1339–1354 (2021). https://doi.org/10.1007/s10571-020-00906-2
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DOI: https://doi.org/10.1007/s10571-020-00906-2