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Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase

Abstract

Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for β-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-β 1–42 (Aβ 1–42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Aβ 1–42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease–associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Aβ 1–42 in Alzheimer's disease.

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Figure 1: Genomic organization and expression analysis of BACE1 and BACE1-AS.
Figure 2: BACE1-AS regulates BACE1 mRNA and protein expression in vitro.
Figure 3: Bace1-AS regulates Bace1 in vivo.
Figure 4: Effect of cell stressors on BACE1 and BACE1-AS.
Figure 5: BACE1-AS increases the stability of BACE1 mRNA.
Figure 6: BACE1-AS and BACE1 expression is elevated in the brain of individuals with Alzheimer's disease.

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Acknowledgements

We thank J. Rogers (Sun Health Research Institute) for autopsy brain tissue. We are grateful to M. Leissring (Mayo Clinic) for helpful discussions and for kindly providing cell lines and APP- tg19959 mouse materials. We also thank D. Willoughby for his help in RNA purification from human Alzheimer's disease samples. S. Brothers provided valuable help in manuscript preparation. M.A.F. is partly supported by a scholarship from the Ahwaz University of Medical Sciences, Ministry of Health I.R. Iran. This study has been supported in part by the US National Institutes of Health (AG 029290).

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C.W., M.A.F., P.J.K. and G.S.L. conceived and designed the experiments and analyzed the data. M.A.F., F.M., P.J.K. and A.M.K. performed the experiments. D.E.W., B.G.S., T.E.M. and C.E.F. provided human Alzheimer's disease RNA samples. M.A.F., C.W., P.J.K. and G.S.L. wrote the paper.

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Correspondence to Claes Wahlestedt.

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Supplementary Figs. 1–6, Supplementary Data 1 and 2, Supplementary Table 1 and Supplementary Methods (PDF 3081 kb)

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Faghihi, M., Modarresi, F., Khalil, A. et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase. Nat Med 14, 723–730 (2008). https://doi.org/10.1038/nm1784

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