CoChat
Sign Up
Cited by 1,183Alzheimer's disease research and treatmentsMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression

Open access
Hébert, Sébastien S., Horré, Katrien, Nicolaï, Laura, Papadopoulou, Aikaterini S., Mandemakers, Wim, Silahtaroglu, Asli N., Kauppinen, Sakari, Delacourte, André +1 more·2008·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0710263105PMC PMC2359789
Open this paper in CoChat — free account

Abstract

Although the role of APP and PSEN genes in genetic Alzheimer's disease (AD) cases is well established, fairly little is known about the molecular mechanisms affecting Aβ generation in sporadic AD. Deficiency in Aβ clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/β-secretase may also be associated with the disease. We therefore investigated changes in microRNA (miRNA) expression profiles of sporadic AD patients and found that several miRNAs potentially involved in the regulation of APP and BACE1 expression appeared to be decreased in diseased brain. We show here that miR-29a, -29b-1, and -9 can regulate BACE1 expression in vitro . The miR-29a/b-1 cluster was significantly (and AD-dementia-specific) decreased in AD patients displaying abnormally high BACE1 protein. Similar correlations between expression of this cluster and BACE1 were found during brain development and in primary neuronal cultures. Finally, we provide evidence for a potential causal relationship between miR-29a/b-1 expression and Aβ generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and Aβ levels in sporadic AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.0710263105

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Up-regulation of BACE1 protein levels during aging is not due to the change of its mRNA levels.

    “However, up-regulation of BACE1 protein levels during aging is not due to the change of its mRNA levels (Hebert et al. 2008, Boissonneault et al. 2009).”

    From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Hebert et al. 2008

    The Results report increased BACE1 protein in a subgroup of sporadic Alzheimer’s disease patients while BACE1 mRNA remained essentially unchanged. The separate Results passage on brain development also reports stable BACE1 mRNA, but neither finding establishes that BACE1 protein increases during aging. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • BACE1 expression is elevated in cortices of AD patients compared to age-matched, non-demented controls.

    “Post-mortem analyses revealed that BACE1 expression is elevated in cortices of AD patients compared to the age-matched, non-demented controls (Fukumoto et al. 2002, Yang et al. 2003, Hebert et al. 2008, Ahmed et al. 2010).”

    From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Hebert et al. 2008

    The Results report significantly higher BACE1 protein in anterior temporal cortex samples from 34 sporadic AD patients than from 21 controls, driven by 11 patients with particularly high levels. The paper calls five controls in an earlier miRNA pilot study age-matched, but our copy does not establish that the 21 controls in the BACE1 comparison were age-matched and non-demented. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Several miRNAs regulating BACE1 expression are down-regulated in the affected regions of AD brains.

    “Among those, several miRNAs regulating BACE1 expression are known to be down-regulated in the affected regions of AD brains (Hebert et al. 2008, Nelson & Wang 2010, Long et al. 2014, Lau et al. 2013).”

    From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Hebert et al. 2008

    The Results report that miR-29a and miR-29b-1 regulate BACE1 and are significantly reduced in anterior temporal cortex from a subgroup of AD patients with high BACE1. The claim omits that subgroup limitation: miR-9 showed only a nonsignificant tendency to decrease, and the Discussion says miR-29a/b-1 loss was not confined to AD-affected regions. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Dysregulation of miRNAs is an important driver of AD progression, directly and indirectly influencing amyloidogenesis, tau hyperphosphorylation, and neuroinflammation.

    “Dysregulation of these miRNAs is now recognized as an important driver of AD progression, directly and indirectly influencing core pathogenic mechanisms such as amyloidogenesis, tau hyperphosphorylation, and neuroinflammation (Hébert et al., 2008; Salta et al., 2016).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Hébert et al., 2008

    The Abstract reports that reduced miR-29a/b-1 may increase BACE1 and Aβ levels, supporting a link to amyloidogenesis. The Discussion says whether altered miRNA expression is a cause or consequence of AD remains unresolved. Neither section supports the attributed effects on tau hyperphosphorylation or neuroinflammation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • A subset of neuronal miRNAs acts to directly suppress APP and BACE1, functioning as an internal brake on Aβ production.

    “A subset of neuronal miRNAs acts to directly suppress APP and BACE1, functioning as an internal brake on Aβ production (Hébert et al., 2008; Wang et al., 2008).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Hébert et al., 2008

    The Results (BACE1 Is a miRNA Target Gene; Aβ cell-culture experiments) show that miR-29a/b-1 directly suppresses BACE1 and reduces Aβ production in a cell model. The Results (miRNA Profile Analysis) identify only predicted binding sites in APP, not demonstrated direct suppression of APP. The authors also say their experiments in primary neurons were inconclusive, so the demonstrated effect on Aβ production is not specifically established in neurons. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 46

  1. [1]Rovelet-Lecrux A, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38:24–26. doi: 10.1038/ng1718. [DOI] [PubMed] [Google Scholar] · DOI
  2. [2]Sherrington R, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754–760. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  3. [3]Rogaev EI, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775–778. doi: 10.1038/376775a0. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. [4]Annaert W, De Strooper B. A cell biological perspective on Alzheimer's disease. Annu Rev Cell Dev Biol. 2002;18:25–51. doi: 10.1146/annurev.cellbio.18.020402.142302. [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Yang LB, et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 2003;9:3–4. doi: 10.1038/nm0103-3. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  6. [6]Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002;59:1381–1389. doi: 10.1001/archneur.59.9.1381. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Sun A, Koelsch G, Tang J, Bing G. Localization of beta-secretase memapsin 2 in the brain of Alzheimer's patients and normal aged controls. Exp Neurol. 2002;175:10–22. doi: 10.1006/exnr.2002.7875. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Holsinger RM, et al. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol. 2002;51:783–786. doi: 10.1002/ana.10208. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  9. [9]Zhao J, et al. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci. 2007;27:3639–3649. doi: 10.1523/JNEUROSCI.4396-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  10. [10]Tesco G, et al. Depletion of GGA3 Stabilizes BACE and Enhances beta-Secretase Activity. Neuron. 2007;54:721–737. doi: 10.1016/j.neuron.2007.05.012. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  11. [11]Li R, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad Sci USA. 2004;101:3632–3637. doi: 10.1073/pnas.0205689101. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. [12]Miska EA, et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol. 2004;5:R68. doi: 10.1186/gb-2004-5-9-r68. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  13. [14]Barad O, et al. MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res. 2004;14:2486–2494. doi: 10.1101/gr.2845604. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  14. [15]Hohjoh H, Fukushima T. Expression profile analysis of microRNA (miRNA) in mouse central nervous system using a new miRNA detection system that examines hybridization signals at every step of washing. Gene. 2007;391:39–44. doi: 10.1016/j.gene.2006.11.018. [DOI] [PubMed] [Google Scholar] · DOI
  15. [16]Mehler MF, Mattick JS. Non-coding RNAs in the nervous system. J Physiol. 2006;575:333–341. doi: 10.1113/jphysiol.2006.113191. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [17]Schratt GM, et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439:283–289. doi: 10.1038/nature04367. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  17. [18]Hebert SS, De Strooper B. Molecular biology. miRNAs in neurodegeneration. Science. 2007;317:1179–1180. doi: 10.1126/science.1148530. [DOI] [PubMed] [Google Scholar] · DOI
  18. [19]Bilen J, et al. MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol Cell. 2006;24:157–163. doi: 10.1016/j.molcel.2006.07.030. [DOI] [PubMed] [Google Scholar] · DOI
  19. [20]Schaefer A, et al. Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med. 2007;204:1553–1558. doi: 10.1084/jem.20070823. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  20. [21]Kim J, et al. A MicroRNA feedback circuit in midbrain dopamine neurons. Science. 2007;317:1220–1224. doi: 10.1126/science.1140481. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  21. [22]Abel S, et al. The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol. 2004;172:6362–6372. doi: 10.4049/jimmunol.172.10.6362. [DOI] [PubMed] [Google Scholar] · DOI
  22. [23]Chang J, et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may down-regulate the high affinity cationic amino acid transporter CAT-1. RNA Biol. 2004;1:106–113. doi: 10.4161/rna.1.2.1066. [DOI] [PubMed] [Google Scholar] · DOI
  23. [24]Best JD, et al. Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-ox o-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl]-l-alaninamide] J Pharmacol Exp Ther. 2005;313:902–908. doi: 10.1124/jpet.104.081174. [DOI] [PubMed] [Google Scholar] · DOI
  24. [25]Grun D, et al. microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput Biol. 2005;1:e13. doi: 10.1371/journal.pcbi.0010013. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [26]Griffiths-Jones S. The microRNA Registry. Nucleic Acids Res. 2004;32:D109–D111. doi: 10.1093/nar/gkh023. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  26. [27]Hwang HW, Wentzel EA, Mendell JT. A hexanucleotide element directs microRNA nuclear import. Science. 2007;315:97–100. doi: 10.1126/science.1136235. [DOI] [PubMed] [Google Scholar] · DOI
  27. [30]Laird FM, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci. 2005;25:11693–11709. doi: 10.1523/JNEUROSCI.2766-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  28. [31]Creemers JW, et al. Processing of beta-secretase by furin and other members of the proprotein convertase family. J Biol Chem. 2001;276:4211–4217. doi: 10.1074/jbc.M006947200. [DOI] [PubMed] [Google Scholar] · DOI
  29. [32]Dominguez D, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem. 2005;280:30797–30806. doi: 10.1074/jbc.M505249200. [DOI] [PubMed] [Google Scholar] · DOI
  30. [33]Rossner S, Sastre M, Bourne K, Lichtenthaler SF. Transcriptional and translational regulation of BACE1 expression−implications for Alzheimer's disease. Prog Neurobiol. 2006;79:95–111. doi: 10.1016/j.pneurobio.2006.06.001. [DOI] [PubMed] [Google Scholar] · DOI
  31. [34]Sastre M, et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci USA. 2006;103:443–448. doi: 10.1073/pnas.0503839103. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  32. [35]Hartlage-Rubsamen M, et al. Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent. Glia. 2003;41:169–179. doi: 10.1002/glia.10178. [DOI] [PubMed] [Google Scholar] · DOI
  33. [36]Zacchetti D, et al. BACE1 Expression and Activity: Relevance in Alzheimer's Disease. Neurodegener Dis. 2007;4:117–126. doi: 10.1159/000101836. [DOI] [PubMed] [Google Scholar] · DOI
  34. [38]Leuba G, et al. Neuronal and nonneuronal quantitative BACE immunocytochemical expression in the entorhinohippocampal and frontal regions in Alzheimer's disease. Dement Geriatr Cogn Disord. 2005;19:171–183. doi: 10.1159/000083496. [DOI] [PubMed] [Google Scholar] · DOI
  35. [39]Rossner S, et al. Neuronal and glial beta-secretase (BACE) protein expression in transgenic Tg2576 mice with amyloid plaque pathology. J Neurosci Res. 2001;64:437–446. doi: 10.1002/jnr.1095. [DOI] [PubMed] [Google Scholar] · DOI
  36. [40]Boehm M, Slack F. A developmental timing microRNA and its target regulate life span in C. elegans. Science. 2005;310:1954–1957. doi: 10.1126/science.1115596. [DOI] [PubMed] [Google Scholar] · DOI
  37. [41]Fabbri M, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA. 2007;104:15805–15810. doi: 10.1073/pnas.0707628104. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  38. [42]Mattson MP. Methylation and acetylation in nervous system development and neurodegenerative disorders. Ageing Res Rev. 2003;2:329–342. doi: 10.1016/s1568-1637(03)00013-8. [DOI] [PubMed] [Google Scholar] · DOI
  39. [43]Niwa R, Zhou F, Li C, Slack FJ. The expression of the Alzheimer's amyloid precursor protein-like gene is regulated by developmental timing microRNAs and their targets in Caenorhabditis elegans. Dev Biol. 2008;315:418–442. doi: 10.1016/j.ydbio.2007.12.044. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  40. [44]Lu J, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838. doi: 10.1038/nature03702. [DOI] [PubMed] [Google Scholar] · DOI
  41. [45]Lukiw WJ. Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus. Neuroreport. 2007;18:297–300. doi: 10.1097/WNR.0b013e3280148e8b. [DOI] [PubMed] [Google Scholar] · DOI
  42. [46]Hebert SS, et al. Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep. 2006;7:739–745. doi: 10.1038/sj.embor.7400704. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  43. [47]Esselens C, et al. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol. 2004;166:1041–1054. doi: 10.1083/jcb.200406060. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  44. [48]Hebert SS, et al. Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis. 2004;17:260–272. doi: 10.1016/j.nbd.2004.08.002. [DOI] [PubMed] [Google Scholar] · DOI
  45. [49]Silahtaroglu AN, et al. Detection of microRNAs in frozen tissue sections by fluorescence in situ hybridization using locked nucleic acid probes and tyramide signal amplification. Nat Protoc. 2007;2:2520–2528. doi: 10.1038/nprot.2007.313. [DOI] [PubMed] [Google Scholar] · DOI
  46. [50]Wang WX, et al. The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci. 2008;28:1213–1223. doi: 10.1523/JNEUROSCI.5065-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Hébert, S. S., Horré, K., Nicolaï, L., Papadopoulou, A. S., Mandemakers, W., Silahtaroglu, A. N., Kauppinen, S., Delacourte, A., & De Strooper, B.
Affiliations
  • KU Leuven (BE)
  • University of Copenhagen (DK)
  • Inserm (FR)
  • *Center for Human Genetics, Katholieke Universiteit Leuven and
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2008-04-29
Volume
105
Issue
17
Pages
6415-6420
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0710263105
PMC
PMC2359789
OpenAlex
W2120522615
Cited by
1,183
References
4
Citations by year
2026: 35 · 2025: 47 · 2024: 49 · 2023: 50 · 2022: 59 · 2021: 77 · 2020: 76 · 2019: 66 · 2018: 65 · 2017: 67 · 2016: 81 · 2015: 79 · 2014: 80 · 2013: 83 · 2012: 57
FWCI
47.98
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
sporadic Alzheimer's disease, miR-29a, miR-9, BACE1, beta-secretase, amyloid-beta production, APP, miRNA expression profiling, brain development, neuronal culture
MeSH terms
Alzheimer Disease, Animals, Brain, Cell Line, Humans, Up-Regulation, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Gene Expression Regulation, Developmental, Gene Expression Profiling, MicroRNAs, Mice, Amyloid Precursor Protein Secretases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review