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Synaptosome microRNAs regulate synapse functions in Alzheimer’s disease

Kumar, Subodh, Orlov, Erika, Gowda, Prashanth, Bose, Chhanda, Swerdlow, Russell H., Lahiri, Debomoy K., Reddy, P. Hemachandra·2022·npj Genomic Medicine
DOI 10.1038/s41525-022-00319-8PMC PMC9359989

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Abstract

MicroRNAs (miRNAs) are found in nerve terminals, synaptic vesicles, and synaptosomes, but it is unclear whether synaptic and cytosolic miRNA populations differ in Alzheimer’s disease (AD) or if synaptosomal miRNAs affect AD synapse activity. To address these questions, we generated synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples and analyzed them using a global Affymetrix miRNAs microarray platform. A group of miRNAs significantly differed ( P < 0.0001) with high fold changes variance (+/− >200-fold) in their expressions in different comparisons: (1) UC synaptosome vs UC cytosol, (2) AD synaptosomes vs AD cytosol, (3) AD cytosol vs UC cytosol, and (4) AD synaptosomes vs UC synaptosomes. MiRNAs data analysis revealed that some potential miRNAs were consistently different across sample groups. These differentially expressed miRNAs were further validated using AD postmortem brains, brains of APP transgenic (Tg2576), Tau transgenic (P301L), and wild-type mice. The miR-501-3p, miR-502-3p, and miR-877-5p were identified as potential synaptosomal miRNAs upregulated with disease progression based on AD Braak stages. Gene Ontology Enrichment and Ingenuity Pathway Analysis of synaptosomal miRNAs showed the involvement of miRNAs in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. This is the first description of synaptic versus cytosolic miRNAs in AD and their significance in synapse function.

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  • miRNAs are trafficked between CNS cell types via EVs/exosomes and potentially synaptosomal compartments, enabling long-range post-transcriptional signaling across neural circuits.

    “MiRNAs are trafficked between CNS cell types via EVs/exosomes and potentially synaptosomal compartments, enabling long-range post-transcriptional signaling across neural circuits (Kumar et al., 2022; Men et al., 2019; Walgrave et al., 2021b).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Kumar et al., 2022

  • miRNAs can be transferred between cells via EVs and other carriers, enabling them to act as intercellular signaling molecules that propagate or mitigate pathology across the CNS.

    “Notably, miRNAs can be transferred between cells via EVs and other carriers, enabling them to act as intercellular signaling molecules that propagate or mitigate pathology across the CNS (Kumar et al., 2022; Men et al., 2019; Walgrave et al., 2021b).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Kumar et al., 2022

  • Many miRNAs function as multifunctional regulators across a complex intercellular network in the brain, not confined to a single cell type.

    “Growing evidence indicates that many miRNAs are not confined to a single cell type but function as multifunctional regulators across a complex intercellular network in the brain (Kumar et al., 2022; Men et al., 2019; Salta et al., 2016; Walgrave et al., 2021b).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Kumar et al., 2022

  • The distinct cell-type and stage-specific miRNA signatures in AD likely reflect a combination of cell-type-restricted transcription factor networks, differences in pri-miRNA processing/Dicer/Argonaute loading, subcellular localization of miRNAs, and selective EV packaging/uptake varying by donor and recipient cell type.

    “This likely reflects a combination of factors: (i) cell-type–restricted transcription factor networks that regulate primary miRNA transcription; (ii) differences in primary microRNA (pri-miRNA) processing, Dicer activity, and Argonaute loading; (iii) subcellular localization of miRNAs to synapses, myelin, or perivascular end-feet; and (iv) selective packaging and uptake of miRNAs into EVs”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Kumar et al., 2022

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Research works printed but not linked: 63

  1. [1]Alzheimer’s disease facts and figures. Alzheimers Dement. 17, 327–406 (2021). 33756057
  2. [2]Forner S Baglietto-Vargas D Martini AC Trujillo-Estrada L LaFerla FM Synaptic impairment in Alzheimer’s disease: a dysregulated symphony Trends Neurosci. 2017 40 347 357 10.1016/j.tins.2017.04.002 28494972 · DOI · Paper page
  3. [3]Marsh J Alifragis P Synaptic dysfunction in Alzheimer’s disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention Neural Regen. Res. 2018 13 616 623 10.4103/1673-5374.230276 29722304 PMC5950662 · DOI
  4. [4]Kashyap G Synapse loss and progress of Alzheimer’s disease—a network model Sci. Rep. 2019 9 6555 10.1038/s41598-019-43076-y 31024073 PMC6484103 · DOI
  5. [5]Selkoe DJ Alzheimer’s disease is a synaptic failure Science 2002 298 789 791 10.1126/science.1074069 12399581 · DOI · Paper page
  6. [6]Chen Y Fu AKY Ip NY Synaptic dysfunction in Alzheimer’s disease: mechanisms and therapeutic strategies Pharmacol. Ther. 2019 195 186 198 10.1016/j.pharmthera.2018.11.006 30439458 · DOI · Paper page
  7. [7]Ahmad F Liu P Synaptosome as a tool in Alzheimer’s disease research Brain Res. 2020 1746 147009 10.1016/j.brainres.2020.147009 32659233 · DOI
  8. [8]Colom-Cadena M The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease Alzheimers Res. Ther. 2020 12 21 10.1186/s13195-020-00588-4 32122400 PMC7053087 · DOI · Paper page
  9. [9]Kumar S Reddy PH The role of synaptic microRNAs in Alzheimer’s disease Biochim. Biophys. Acta Mol. Basis Dis. 2020 1866 165937 10.1016/j.bbadis.2020.165937 32827646 PMC7680400 · DOI
  10. [11]Spires-Jones TL Hyman BT The intersection of amyloid beta and tau at synapses in Alzheimer’s disease Neuron 2014 82 756 771 10.1016/j.neuron.2014.05.004 24853936 PMC4135182 · DOI · Paper page
  11. [13]Calkins MJ Manczak M Mao P Shirendeb U Reddy PH Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease Hum. Mol. Genet. 2011 20 4515 4529 10.1093/hmg/ddr381 21873260 PMC3209824 · DOI · Paper page
  12. [14]Calkins MJ Manczak M Reddy PH Mitochondria-targeted antioxidant SS31 prevents amyloid beta-induced mitochondrial abnormalities and synaptic degeneration in Alzheimer’s disease Pharmaceuticals 2012 5 1103 1119 10.3390/ph5101103 23226091 PMC3513393 · DOI
  13. [15]Swerdlow RH The mitochondrial hypothesis: dysfunction, bioenergetic defects, and the metabolic link to Alzheimer’s disease Int. Rev. Neurobiol. 2020 154 207 233 10.1016/bs.irn.2020.01.008 32739005 PMC8493961 · DOI
  14. [16]Weidling IW Swerdlow RH Mitochondria in Alzheimer’s disease and their potential role in Alzheimer’s proteostasis Exp. Neurol. 2020 330 113321 10.1016/j.expneurol.2020.113321 32339611 PMC7282957 · DOI
  15. [17]Kodavati M Wang H Hegde ML Altered mitochondrial dynamics in motor neuron disease: an emerging perspective Cells 2020 9 1065 10.3390/cells9041065 PMC7226538 32344665 · DOI
  16. [18]Ammal KN Ahuja M Sharma SM Thomas B An emerging role of miRNAs in neurodegenerative diseases: mechanisms and perspectives on miR146a Antioxid. Redox Signal 2021 35 580 594 10.1089/ars.2020.8256 33403895 PMC8388248 · DOI
  17. [19]John A Reddy PH Synaptic basis of Alzheimer’s disease: focus on synaptic amyloid beta, P-tau and mitochondria Ageing Res. Rev. 2021 65 101208 10.1016/j.arr.2020.101208 33157321 PMC7770124 · DOI · Paper page
  18. [21]Lugli G Torvik VI Larson J Smalheiser NR Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain J. Neurochem. 2008 106 650 661 10.1111/j.1471-4159.2008.05413.x 18410515 PMC3711666 · DOI · Paper page
  19. [22]Xu J Chen Q Zen K Zhang C Zhang Q Synaptosomes secrete and uptake functionally active microRNAs via exocytosis and endocytosis pathways J. Neurochem. 2013 124 15 25 10.1111/jnc.12057 23083096 · DOI · Paper page
  20. [23]Li H Wu C Aramayo R Sachs MS Harlow ML Synaptic vesicles contain small ribonucleic acids (sRNAs) including transfer RNA fragments (trfRNA) and microRNAs (miRNA) Sci. Rep. 2015 5 14918 10.1038/srep14918 26446566 PMC4597359 · DOI
  21. [24]Boese AS MicroRNA abundance is altered in synaptoneurosomes during prion disease Mol. Cell. Neurosci. 2016 71 13 24 10.1016/j.mcn.2015.12.001 26658803 · DOI
  22. [25]Rylett RJ Ball MJ Colhoun EH Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer’s disease Brain Res. 1983 289 169 175 10.1016/0006-8993(83)90017-3 6661641 · DOI
  23. [26]Rajmohan R Reddy PH Amyloid-beta and phosphorylated Tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons J. Alzheimers Dis. 2017 57 975 999 10.3233/JAD-160612 27567878 PMC5793225 · DOI
  24. [27]Lauterborn JC Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease Nat. Commun. 2021 12 2603 10.1038/s41467-021-22742-8 33972518 PMC8110554 · DOI
  25. [29]Hollnagel JO Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis PLoS ONE 2019 14 e0209228 10.1371/journal.pone.0209228 30645585 PMC6333398 · DOI
  26. [30]Xu Y Zhao M Han Y Zhang H GABAergic inhibitory interneuron deficits in Alzheimer’s disease: implications for treatment Front. Neurosci. 2020 14 660 10.3389/fnins.2020.00660 32714136 PMC7344222 · DOI · Paper page
  27. [31]Jiménez-Balado J Eich TS GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease Semin. Cell Dev. Biol. 2021 116 146 159 10.1016/j.semcdb.2021.01.005 33573856 PMC8292162 · DOI
  28. [32]Jhou JF Tai HC The study of postmortem human synaptosomes for understanding Alzheimer’s disease and other neurological disorders: a review Neurol. Ther. 2017 6 57 68 10.1007/s40120-017-0070-z 28733958 PMC5520816 · DOI
  29. [33]Schratt G microRNAs at the synapse Nat. Rev. Neurosci. 2009 10 842 849 10.1038/nrn2763 19888283 · DOI · Paper page
  30. [34]Siegel G Saba R Schratt G microRNAs in neurons: manifold regulatory roles at the synapse Curr. Opin. Genet. Dev. 2011 21 491 497 10.1016/j.gde.2011.04.008 21561760 · DOI
  31. [35]Wingo TS Brain microRNAs associated with late-life depressive symptoms are also associated with cognitive trajectory and dementia npj Genom. Med. 2020 5 6 10.1038/s41525-019-0113-8 32047652 PMC7004995 · DOI
  32. [36]Reddy PH Beal MF Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease Trends Mol. Med. 2008 14 45 53 10.1016/j.molmed.2007.12.002 18218341 PMC3107703 · DOI · Paper page
  33. [37]Smalheiser NR The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity Philos. Trans. R. Soc. Lond. B. Biol. Sci. 2014 369 20130504 10.1098/rstb.2013.0504 25135965 PMC4142025 · DOI
  34. [38]Ye Y Xu H Su X He X Role of microRNA in governing synaptic plasticity Neural Plast. 2016 2016 4959523 27034846 PMC4808557
  35. [39]John A Kubosumi A Reddy PH Mitochondrial microRNAs in aging and neurodegenerative diseases Cells 2020 9 1345 10.3390/cells9061345 PMC7349858 32481587 · DOI
  36. [40]Gowda, P., Reddy, P. H. & Kumar, S. Deregulated mitochondrial microRNAs in Alzheimer’s disease: focus on synapse and mitochondria. Aging Res. Review. 73, 101529 (2021). PMC8692431 34813976
  37. [41]Lahiri DK Maloney B Beyond the signaling effect role of amyloid-ß42 on the processing of APP, and its clinical implications Exp. Neurol. 2010 225 51 54 10.1016/j.expneurol.2010.04.018 20451519 PMC2922469 · DOI
  38. [42]Long JM Lahiri DK MicroRNA-101 downregulates Alzheimer’s amyloid-β precursor protein levels in human cell cultures and is differentially expressed Biochem. Biophys. Res. Commun. 2011 404 88995 10.1016/j.bbrc.2010.12.053 PMC3372402 21172309 · DOI
  39. [43]Long JM Maloney B Rogers JT Lahiri DK Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: implications in Alzheimer’s disease Mol. Psychiatry 2019 3 345 463 10.1038/s41380-018-0266-3 PMC6514885 30470799 · DOI · Paper page
  40. [44]Chopra N MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties Mol. Psychiatry 2021 26 5636 5657 10.1038/s41380-019-0610-2 31942037 PMC8758483 · DOI
  41. [45]Lukiw WJ microRNA-146a signaling in Alzheimer’s disease (AD) and prion disease (PrD) Front. Neurol. 2020 25 462 10.3389/fneur.2020.00462 PMC7331828 32670176 · DOI
  42. [46]Zhao Y Jaber VR LeBeauf A Sharfman NM Lukiw WJ microRNA-34a (miRNA-34a) mediated down-regulation of the post-synaptic cytoskeletal element SHANK3 in sporadic Alzheimer’s disease (AD) Front. Neurol. 2019 10 28 10.3389/fneur.2019.00028 30792687 PMC6374620 · DOI
  43. [47]Kumar S Reddy PH Are circulating microRNAs peripheral biomarkers for Alzheimer’s disease? Biochim. Biophys. Acta 2016 1862 1617 1627 10.1016/j.bbadis.2016.06.001 27264337 PMC5343750 · DOI
  44. [48]Zolochevska O Taglialatela G Selected microRNAs increase synaptic resilience to the damaging binding of the Alzheimer’s disease amyloid beta oligomers Mol. Neurobiol. 2020 57 2232 2243 10.1007/s12035-020-01868-8 31997075 PMC7170988 · DOI
  45. [49]Yoshino Y Roy B Dwivedi Y Differential and unique patterns of synaptic miRNA expression in dorsolateral prefrontal cortex of depressed subjects Neuropsychopharmacology 2021 46 900 910 10.1038/s41386-020-00861-y 32919404 PMC8115313 · DOI
  46. [50]Scherma M Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine Proc. Natl Acad. Sci. USA 2020 117 9991 10002 10.1073/pnas.1920866117 32312805 PMC7211986 · DOI
  47. [51]Hebb CO Whittaker VP Intracellular distributions of acetylcholine and choline acetylase J. Physiol. 1958 142 187 196 10.1113/jphysiol.1958.sp006008 13564428 PMC1356703 · DOI
  48. [52]Jie M Subcellular localization of miRNAs and implications in cellular homeostasis Genes (Basel) 2021 12 856 10.3390/genes12060856 34199614 PMC8226975 · DOI
  49. [53]Kang Q MiR-124-3p attenuates hyperphosphorylation of Tau protein-induced apoptosis via caveolin-1-PI3K/Akt/GSK3β pathway in N2a/APP695swe cells Oncotarget 2017 8 24314 24326 10.18632/oncotarget.15149 28186985 PMC5421849 · DOI
  50. [54]Hara N Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer’s disease Acta Neuropathol. Commun. 2017 5 10 10.1186/s40478-017-0414-z 28137310 PMC5282710 · DOI
  51. [55]Yang H Wang H Shu Y Li X miR-103 promotes neurite outgrowth and suppresses cells apoptosis by targeting prostaglandin-endoperoxide synthase 2 in cellular models of Alzheimer’s disease Front. Cell Neurosci. 2018 12 91 10.3389/fncel.2018.00091 29674956 PMC5895658 · DOI
  52. [56]Boscher E MicroRNA-138 overexpression alters Aβ42 levels and behavior in wildtype mice Front. Neurosci. 2021 14 591138 10.3389/fnins.2020.591138 33519353 PMC7840584 · DOI
  53. [57]Estfanous S Elevated expression of MiR-17 in microglia of Alzheimer’s disease patients abrogates autophagy-mediated amyloid-β degradation Front. Immunol. 2021 12 705581 10.3389/fimmu.2021.705581 34426734 PMC8379081 · DOI
  54. [58]Liang C MicroRNA-140 silencing represses the incidence of Alzheimer’s disease Neurosci. Lett. 2021 758 135674 10.1016/j.neulet.2021.135674 33529652 · DOI · Paper page
  55. [59]Kumar S Reddy PH MicroRNA-455-3p as a potential biomarker for Alzheimer’s disease: an update Front. Aging Neurosci. 2018 10 41 10.3389/fnagi.2018.00041 29527164 PMC5829054 · DOI
  56. [60]Franklin W Taglialatela G A method to determine insulin responsiveness in synaptosomes isolated from frozen brain tissue J. Neurosci. Methods 2016 261 128 134 10.1016/j.jneumeth.2016.01.006 26774027 PMC4749422 · DOI
  57. [61]Biesemann C Proteomic screening of glutamatergic mouse brain synaptosomes isolated by fluorescence activated sorting EMBO J. 2014 33 157 170 10.1002/embj.201386120 24413018 PMC3989609 · DOI · Paper page
  58. [62]Postupna NO Flow cytometry analysis of synaptosomes from post-mortem human brain reveals changes specific to Lewy body and Alzheimer’s disease Lab. Investig. 2014 94 1161 1172 10.1038/labinvest.2014.103 25068655 PMC4184945 · DOI
  59. [63]Kumar S Reddy AP Yin X Reddy PH Novel microRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer’s disease Biochim. Biophys. Acta Mol. Basis Dis. 2019 1865 2428 2440 10.1016/j.bbadis.2019.06.006 31181293 PMC6688505 · DOI
  60. [65]Kumar S Chawla YK Ghosh S Chakraborti A Severity of hepatitis C virus (genotype-3) infection positively correlates with circulating microRNA-122 in patients sera Dis. Markers 2014 2014 435476 10.1155/2014/435476 24696531 PMC3948614 · DOI
  61. [66]Kumar S Vijayan M Reddy PH MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer’s disease Hum. Mol. Genet. 2017 26 3808 3822 10.1093/hmg/ddx267 28934394 PMC6075184 · DOI · Paper page
  62. [67]Kumar S Reddy PH Elevated levels of MicroRNA-455-3p in the cerebrospinal fluid of Alzheimer’s patients: a potential biomarker for Alzheimer’s disease Biochim. Biophys. Acta Mol. Basis Dis. 2021 1867 166052 10.1016/j.bbadis.2020.166052 33412267 PMC7867567 · DOI
  63. [68]Vijayan M Identification of novel circulatory microRNA signatures linked to patients with ischemic stroke Hum. Mol. Genet. 2018 27 2318 2329 10.1093/hmg/ddy136 29701837 PMC6005038 · DOI

Cited by

Sorted by citations

Authors
Kumar, S., Orlov, E., Gowda, P., Bose, C., Swerdlow, R. H., Lahiri, D. K., & Reddy, P. H.
Venue
npj Genomic Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-08-08
Volume
7
Issue
1
ISSN
2056-7944
DOI
10.1038/s41525-022-00319-8
PMC
PMC9359989
Cited by
45
References
5
Language
en
Licence
Funders
U.S. Department of Health & Human Services | NIH | Center for Scientific Review (K99AG65645, AG072973, AG051086, AG069333)

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