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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The datasets analyzed during the current study are available upon request with no restriction.
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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This article has been retracted.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
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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