Metabolic Brain Disease

, Volume 33, Issue 5, pp 1711–1720 | Cite as

Comparative study of microRNA profiling in one Chinese Family with PSEN1 G378E mutation

  • Zhanyun Lv
  • Liangchen Hu
  • Yan Yang
  • Kui Zhang
  • Zuzhen Sun
  • Jing Zhang
  • Lipan Zhang
  • Yanlei HaoEmail author
Original Article


MicroRNAs are not widely studied in familial Alzheimer’s disease cases, whether the microRNA profilings in familial Alzheimer’s disease patients are similar to the sporadic AD patients is not known. This study aims to investigate the differential expression of microRNAs (miRNAs) associated with early-onset familial Alzheimer’s disease (EO-FAD) in a Chinese family. We performed the gene mutation analysis in a family clinically diagnosed of EO-FAD. Micro-arrays were used to profile the miRNAs in cerebrospinal fluid of 2 affected members, 2 unaffected carriers and 2 mutation negative controls. The clinical presentation confirmed the EO-FAD diagnosis, and a recurrent mutation of the PSEN1 p.G378E was found in the family. The result showed that in the miRNAs expression profile, a total of 166 miRNAs were up-regulated and 3 miRNAs were down-regulated in the affected individuals compared with mutation negative individuals. But after Benjamini Hochberg FDR correction, only 25 miRNAs were significantly up-regulated and no miRNA was down-regulated, the levels of miR-30a-5p, miR-4758-3p and let-7a-3p were elevated significantly. Compared with mutation negative controls, 21 miRNAs were up-regulated and 18 microRNAs were down-regulated in the unaffected mutation carriers, after Benjamini Hochberg FDR correction, miR-345-5p was up-regulated and miR-4795-3p was down-regulated in the unaffected mutation carriers. And there was no difference between the affected members and unaffected mutation carriers. GO database showed that the top biological processes affected by the predicted target genes are nucleic acid binding transcription factor activity and transcription factor activity (sequence-specific DNA binding) (GO:0001071 and GO:0003700). The result of KEGG pathways showed 64 pathways were implicated in the regulatory network. The present study identified the miRNA profiling of Chinese siblings with G378E mutation in the PSEN1. Compared with mutation negative controls, the levels of 25 miRNAs including miR-30a-5p, miR-4758-3p and let-7a-3p were elevated significantly in the affected members, miR-345-5p was up-regulated and miR-4795-3p was down-regulated in the unaffected mutation carriers. Our study showed the microRNA profilings in the cases of a EO-FAD family with PSEN1 p.G378E mutation, but because of the individuals in the family was small, the results in other types of EO-FAD still need further studied.


EO-FAD microRNA profiling miR-30-5p miR-4758-3p Let-7a-3p FOXO signaling pathway 





early-onset familial Alzheimer’s disease


magnetic resonance imaging


Alzheimer’s disease


neurofibrillary tangles


cerebrospinal fluid


sporadic AD


Familial AD


amyloid precursor protein


presenilin 1


presenilin 2


Mini- Mental State Examination


instrumental activities of daily living scales


false discovery rate


toll-like receptor 7


Kyoto Encyclopedia of Genes and Genomes


Notch1 intercellular domain



We would like to thank the patients for their participation in this study.

Authors’ contributions

Lv ZY and Hu LC contributed equally in RNA extraction and microRNA analysis. Zhang K, Sun ZZ, Zhang J, Zhang LP and Yang Y interviewed the patients and their family members, collected clinical data and CSF and blood samples. Hao YL was a major contributor in writing the manuscript. All authors read and approved the final manuscript.


This study was supported by the National Natural Science Foundation of China (grant No. 81401064, NO.81771360); PhD initial funding (2016-BS-011); Jining science and technology development project (Jikezi [2016]56–6) and Natural Science Foundation of Shandong (ZR2017LH031).

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Written informed consent for publication was obtained from patients. A copy of the written consent is available for review to the Editor of this journal.

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committees of the Affiliated Hospital of Jining Medical University, and all participants provided written informed consent.

Supplementary material

11011_2018_279_MOESM1_ESM.docx (28 kb)
ESM 1 (DOCX 27 kb)
11011_2018_279_MOESM2_ESM.docx (39 kb)
ESM 2 (DOCX 38 kb)


  1. Bekris LM, Leverenz JB (2015) The biomarker and therapeutic potential of miRNA in Alzheimer's disease. Neurodegener Dis Manag 5:61–74CrossRefPubMedGoogle Scholar
  2. Besancon R, Lorenzi A, Cruts M, Radawiec S, Sturtz F, Broussolle E et al (1998) Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Mutations in brief no. 141. Online. Hum Mutat 11:481CrossRefPubMedGoogle Scholar
  3. Burgos K, Malenica I, Metpally R, Courtright A, Rakela B, Beach T, Shill H, Adler C, Sabbagh M, Villa S, Tembe W, Craig D, van Keuren-Jensen K (2014) Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology. PLoS One 9:e94839CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chen PS, Su JL, Cha ST, Tarn WY, Wang MY, Hsu HC, Lin MT, Chu CY, Hua KT, Chen CN, Kuo TC, Chang KJ, Hsiao M, Chang YW, Chen JS, Yang PC, Kuo ML (2011) miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans. J Clin Invest 121:3442–3455CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cornejo-Olivas MR, Yu CE, Mazzetti P, Mata IF, Meza M, Lindo-Samanamud S, Leverenz JB, Bird TD (2014) Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease. Neurosci Lett 563:140–143CrossRefPubMedPubMedCentralGoogle Scholar
  6. Croce N, Gelfo F, Ciotti MT, Federici G, Caltagirone C, Bernardini S, Angelucci F (2013 Apr) NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection? Mol Cell Biochem 376(1–2):189–195CrossRefPubMedGoogle Scholar
  7. Dorszewska J, Prendecki M, Oczkowska A, Dezor M, Kozubski W (2016) Molecular basis of familial and sporadic Alzheimer's disease. Curr Alzheimer Res 13:952–963CrossRefPubMedGoogle Scholar
  8. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K et al (2014) Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol 13:614–629CrossRefPubMedGoogle Scholar
  9. Erener S, Marwaha A, Tan R, Panagiotopoulos C, Kieffer TJ (2017 Feb 23) Profiling of circulating microRNAs in children with recent onset of type 1 diabetes. JCI Insight 2(4):e89656CrossRefPubMedPubMedCentralGoogle Scholar
  10. Fernandez AM, Hervas R, Dominguez-Fraile M, Garrido VN, Gomez-Gutierrez P, Vega M, Vitorica J, Perez JJ, Torres Aleman I (2016 Apr 12) Blockade of the interaction of Calcineurin with FOXO in astrocytes protects against amyloid-β-induced neuronal death. J Alzheimers Dis 52(4):1471–1478CrossRefPubMedGoogle Scholar
  11. Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A (2005) Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics 6:85–89CrossRefPubMedGoogle Scholar
  12. Gui Y, Liu H, Zhang L, Lv W, Hu X (2015) Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 6:37043–37053CrossRefPubMedPubMedCentralGoogle Scholar
  13. Guo Y, Sun W, Gong T, Chai Y, Wang J, Hui B et al (2017 Feb 14) miR-30a radiosensitizes non-small cell lung cancer by targeting ATF1 that is involved in the phosphorylation of ATM. Oncol RepGoogle Scholar
  14. Han X, Zhen S, Ye Z, Lu J, Wang L, Li P, Li J, Zheng X, Li H, Chen W, Zhao L, Li X (2017 Feb 21) A feedback loop between miR-30a/c-5p and DNMT1 mediates cisplatin resistance in ovarian Cancer cells. Cell Physiol Biochem 41(3):973–986CrossRefPubMedGoogle Scholar
  15. Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, de Strooper B (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 105:6415–6420CrossRefPubMedPubMedCentralGoogle Scholar
  16. Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, Tsuchiya M, Imamura T, Ishizu H, Aoki K, Ishikawa A, Onodera O, Kuwano R, Nishizawa M (2008) Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord 26:43–49CrossRefPubMedGoogle Scholar
  17. Jayadev S, Case A, Alajajian B, Eastman AJ, Moller T, Garden GA (2013) Presenilin 2 influences miR146 level and activity in microglia. J Neurochem 127:592–599CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kiko T, Nakagawa K, Tsuduki T, Furukawa K, Arai H, Miyazawa T (2014) MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer's disease. J Alzheimers Dis 39:253–259CrossRefPubMedGoogle Scholar
  19. Lehmann SM, Kruger C, Park B, Derkow K, Rosenberger K, Baumgart J et al (2012) An unconventional role for miRNA: let-7 activates toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835CrossRefPubMedGoogle Scholar
  20. Lei X, Lei L, Zhang Z, Zhang Z, Cheng Y (2015) Downregulated miR-29c correlates with increased BACE1 expression in sporadic Alzheimer's disease. Int J Clin Exp Pathol 8:1565–1574PubMedPubMedCentralGoogle Scholar
  21. Li Y, Zhang T, Zhou Y, Sun Y, Cao Y, Chang X, Zhu Y, Han X (2016 Nov 2) A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis. Sci Rep 6:36136CrossRefPubMedPubMedCentralGoogle Scholar
  22. Lukiw WJ, Andreeva TV, Grigorenko AP, Rogaev EI (2012) Studying micro RNA function and dysfunction in Alzheimer's disease. Front Genet 3:327CrossRefPubMedGoogle Scholar
  23. Luo H, Wu Q, Ye X, Xiong Y, Zhu J, Xu J, Diao Y, Zhang D, Wang M, Qiu J, Miao J, Zhang W, Wan J (2014 Aug 22) Genome-wide analysis of miRNA signature in the APPswe/PS1ΔE9 mouse model of alzheimer'sdisease. PLoS One 9(8):e101725CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lv Z, Shi Q, Huang W, Xing C, Hao Y, Feng X et al (2016) MicroRNA expression profiling in Guillain-Barré syndrome. J Neuroimmunol 301:12–15CrossRefPubMedGoogle Scholar
  25. Maiese K (2015) FoxO proteins in the nervous system. Anal Cell Pathol (Amst) 2015:569392Google Scholar
  26. Manolopoulos KN, Klotz LO, Korsten P, Bornstein SR, Barthel A (2010 Nov) Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress. Mol Psychiatry 15(11):1046–1052CrossRefPubMedGoogle Scholar
  27. Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S (2008 Oct 1) A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitorsof BDNF in prefrontal cortex. Hum Mol Genet 17(19):3030–3042CrossRefPubMedPubMedCentralGoogle Scholar
  28. Meng F, Wang F, Wang L, Wong SC, Cho WC, Chan LW (2016 Nov 15) MiR-30a-5p overexpression may overcome EGFR-inhibitor resistance through regulating PI3K/AKT signaling pathway in non-small cell lung Cancer cell lines. Front Genet 7:197CrossRefPubMedPubMedCentralGoogle Scholar
  29. Muller M, Kuiperij HB, Claassen JA, Kusters B, Verbeek MM (2014) MicroRNAs in Alzheimer's disease: differential expression in hippocampus and cell-free cerebrospinal fluid. Neurobiol Aging 35:152–158CrossRefPubMedGoogle Scholar
  30. Pan Y, Liu R, Terpstra E, Wang Y, Qiao F, Wang J, Tong Y, Pan B (2015) Dysregulation and diagnostic potential of microRNA in Alzheimer's disease. J Alzheimers Dis 49:1–12CrossRefGoogle Scholar
  31. Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, Ji RR (2014) Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82:47–54CrossRefPubMedPubMedCentralGoogle Scholar
  32. Pugazhenthi S (2017) Metabolic syndrome and the cellular phase of Alzheimer's disease. Prog Mol Biol Transl Sci 146:243–258CrossRefPubMedGoogle Scholar
  33. Quanquan W, Yanlei H, Yan Y, Qingxia K, Shuhu Z, Zhanyun L (2017 march) A Chinese pedigree with early-onset familial Alzheimer’s disease caused by presenilin 1 p.G378E. Chin J Neurol 50(3):208–212Google Scholar
  34. Ren RJ, Zhang YF, Dammer EB, Zhou Y, Wang LL, Liu XH, Feng BL, Jiang GX, Chen SD, Wang G, Cheng Q (2016) Peripheral blood MicroRNA expression profiles in Alzheimer's disease: screening, validation, association with clinical phenotype and implications for molecular mechanism. Mol Neurobiol 53:5772–5781CrossRefPubMedGoogle Scholar
  35. Sajan M, Hansen B, Ivey R. 3rd, Sajan J, Ari C, Song S, et al. Brain insulin signaling is increased in insulin-resistant states and decreases in FOXOs and PGC-1α and increases in Aβ1-40/42 and Phospho-tau may abet Alzheimer development. Diabetes 2016 Jul;65(7):1892–1903CrossRefPubMedPubMedCentralGoogle Scholar
  36. Satoh J, Kino Y, Niida S (2015) MicroRNA-Seq data analysis pipeline to identify blood biomarkers for Alzheimer's disease from public data. Biomark Insights 10:21–31CrossRefPubMedPubMedCentralGoogle Scholar
  37. Shafi O (2016 Nov 22) Inverse relationship between Alzheimer's disease and cancer, and other factors contributing toAlzheimer's disease: a systematic review. BMC Neurol 16(1):236CrossRefPubMedPubMedCentralGoogle Scholar
  38. Shamsuzzama KL, Haque R, Nazir A (2016) Role of MicroRNA Let-7 in modulating multifactorial aspect of neurodegenerative diseases: an overview. Mol Neurobiol 53:2787–2793CrossRefPubMedGoogle Scholar
  39. Song J, Lee JE (2015) miR-155 is involved in Alzheimer's disease by regulating T lymphocyte function. Front Aging Neurosci 7:61CrossRefPubMedPubMedCentralGoogle Scholar
  40. Sorensen SS, Nygaard AB, Christensen T (2016) miRNA expression profiles in cerebrospinal fluid and blood of patients with Alzheimer's disease and other types of dementia - an exploratory study. Transl Neurodegener 5:6CrossRefPubMedPubMedCentralGoogle Scholar
  41. Tai LM, Mehra S, Shete V, Estus S, Rebeck GW, Bu G, LaDu M (2014) Soluble apoE/Abeta complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener 9:2CrossRefPubMedPubMedCentralGoogle Scholar
  42. Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T, Tan L (2014) Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer's disease. J Alzheimers Dis 40:1017–1027CrossRefPubMedGoogle Scholar
  43. Van Giau V, An SS (2016) Emergence of exosomal miRNAs as a diagnostic biomarker for Alzheimer's disease. J Neurol Sci 360:141–152CrossRefPubMedGoogle Scholar
  44. Wei W, Yang Y, Cai J, Cui K, Li RX, Wang H et al (2016) MiR-30a-5p suppresses tumor metastasis of human colorectal Cancer by targeting ITGB3. Cell Physiol Biochem 39(3):1165–1176CrossRefPubMedGoogle Scholar
  45. Zhao Y, Bhattacharjee S, Jones BM, Hill J, Dua P, Lukiw WJ (2014) Regulation of neurotropic signaling by the inducible, NF-kB-sensitive miRNA-125b in Alzheimer's disease (AD) and in primary human neuronal-glial (HNG) cells. Mol Neurobiol 50:97–106CrossRefPubMedGoogle Scholar
  46. Zhao Y, Pogue AI, Lukiw WJ (2015) MicroRNA (miRNA) signaling in the human CNS in sporadic Alzheimer's disease (AD)-novel and unique pathological features. Int J Mol Sci 16:30105–30116CrossRefPubMedPubMedCentralGoogle Scholar
  47. Zhu J, Zeng Y, Li W, Qin H, Lei Z, Shen D, Gu D, Huang JA, Liu Z (2017 Feb 3) CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer. Mol Cancer 16(1):34CrossRefPubMedPubMedCentralGoogle Scholar
  48. Zong Y, Wang H, Dong W, Quan X, Zhu H, Xu Y, Huang L, Ma C, Qin C (2011) miR-29c regulates BACE1 protein expression. Brain Res 1395:108–115CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Zhanyun Lv
    • 1
  • Liangchen Hu
    • 1
  • Yan Yang
    • 1
  • Kui Zhang
    • 1
  • Zuzhen Sun
    • 1
  • Jing Zhang
    • 1
  • Lipan Zhang
    • 1
  • Yanlei Hao
    • 1
    Email author
  1. 1.Department of NeurologyAffiliated Hospital of Jining Medical UniversityJiningChina

Personalised recommendations