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Are pulmonary fibrosis and Alzheimer's disease linked? Shared dysregulation of two miRNA species and downstream pathways accompany both disorders

  • Debomoy K. Lahiri
    Correspondence
    To whom correspondence should be addressed: Indiana University School of Medicine, 320 West 15th St., Indianapolis, IN 46202. Tel.: 317-274-2706; Fax: 317-231-0203
    Affiliations
    Department of Psychiatry, Indiana Alzheimer Disease Center, Stark Neurosciences Research Institute, Indianapolis, Indiana 46202

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
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  • Bryan Maloney
    Affiliations
    Department of Psychiatry, Indiana Alzheimer Disease Center, Stark Neurosciences Research Institute, Indianapolis, Indiana 46202
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  • Nigel H. Greig
    Affiliations
    Translational Gerontology Branch, Intramural Research Program, NIA, National Institutes of Health, Baltimore, Maryland 21224
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Open AccessPublished:December 08, 2017DOI:https://doi.org/10.1074/jbc.L117.000502
      As neuroscientists, we were intrigued when Huang et al. (
      • Huang C.
      • Xiao X.
      • Yang Y.
      • Mishra A.
      • Liang Y.
      • Zeng X.
      • Yang X.
      • Xu D.
      • Blackburn M.R.
      • Henke C.A.
      • Liu L.
      MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation.
      ) reported that miR101 can attenuate pulmonary fibrosis (PF)
      The abbreviations used are: PF
      pulmonary fibrosis
      AD
      Alzheimer's disease
      PPARγ
      peroxisome proliferator–activated receptor γ
      APP
      Aβ-precursor protein.
      2The abbreviations used are: PF
      pulmonary fibrosis
      AD
      Alzheimer's disease
      PPARγ
      peroxisome proliferator–activated receptor γ
      APP
      Aβ-precursor protein.
      through suppression of Wnt family member 5A (WNT5A). Accumulating evidence suggests that prima facie unrelated disorders in multiple fields of medicine share fundamental molecular pathways. For example, PF associates with cognitive impairment (
      • Bors M.
      • Tomic R.
      • Perlman D.M.
      • Kim H.J.
      • Whelan T.P.
      Cognitive function in idiopathic pulmonary fibrosis.
      ). It is reasonable to presume that such links would be due to hypoxia and general inflammation, but could there be a deeper connection? Both miR101 and miR27b expression levels were significantly reduced in more severe PF cases (
      • Huang C.
      • Xiao X.
      • Yang Y.
      • Mishra A.
      • Liang Y.
      • Zeng X.
      • Yang X.
      • Xu D.
      • Blackburn M.R.
      • Henke C.A.
      • Liu L.
      MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation.
      ). These same miRNA are implicated and reduced (
      • Jennewein C.
      • von Knethen A.
      • Schmid T.
      • Brüne B.
      MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor γ (PPARγ) mRNA destabilization.
      ,
      • Long J.M.
      • Lahiri D.K.
      MicroRNA-101 downregulates Alzheimer’s amyloid-β precursor protein levels in human cell cultures and is differentially expressed.
      ) in Alzheimer’s disease (AD). Interestingly, while miR101 levels are reduced in late-stage AD brain samples, an miRNA associated with AD and Parkinson’s disease, miR153, is not (
      • Long J.M.
      • Ray B.
      • Lahiri D.K.
      MicroRNA-153 physiologically inhibits expression of amyloid-β precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients.
      ). Notably, miR27b regulates peroxisome proliferator–activated receptor γ (PPARγ), and PPARγ disruption is implicated in both AD and PF (
      • Jennewein C.
      • von Knethen A.
      • Schmid T.
      • Brüne B.
      MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor γ (PPARγ) mRNA destabilization.
      ). Wnt signaling disruption is a well-known molecular feature of AD (
      • Inestrosa N.C.
      • Varela-Nallar L.
      Wnt signaling in the nervous system and in Alzheimer's disease.
      ). That two miRNA species are both down-regulated and pathways they regulate are linked to specific pulmonary and neurological disorders is noteworthy. If we want to take a broader view of connection or divergence of progressive disorders, we also can consider that miRNAs usually have multiple mRNA targets. In addition to regulating Wnt signaling, miR101 regulates levels of the Aβ-precursor protein (APP) and, by extension, its neurotoxic processing product, Aβ (
      • Long J.M.
      • Lahiri D.K.
      MicroRNA-101 downregulates Alzheimer’s amyloid-β precursor protein levels in human cell cultures and is differentially expressed.
      ). APP, as such, has not been directly implicated in PF, but it would not be unreasonable to propose that disruption of miR101 would impact several vital signaling and expression pathways. Disruption of a fundamental, multiorgan-wide pathway such as Wnt or PPARγ signaling could be a broad precursor to multiple disorders, with specificity to be determined by other interactions. This suggests the potential for developing a therapeutic strategy to utilize common dysregulation of specific miRNAs for disparate diseases.

      Acknowledgments

      We thank Drs. A. Saykin and M. Srinivasan for their advice.

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