Selected MicroRNAs Increase Synaptic Resilience to the Damaging Binding of the Alzheimer's Disease Amyloid Beta Oligomers

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2020 Jan 31

PMID 31997075

Citations 15

Authors

Olga Zolochevska

Giulio Taglialatela

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is marked by synaptic loss (at early stages) and neuronal death (at late stages). Amyloid beta (Aβ) and tau oligomers can target and disrupt synapses thus driving cognitive decay. Non-demented individuals with Alzheimer's neuropathology (NDAN) are capable of withstanding Aβ and tau toxicity, thus remaining cognitively intact despite presence of AD neuropathology. Understanding the involved mechanism(s) would lead to development of novel effective therapeutic strategies aimed at promoting synaptic resilience to amyloid toxicity. NDAN have a unique hippocampal post-synaptic proteome when compared with AD and control individuals. Potential upstream modulators of such unique proteomic profile are miRNA-485, miRNA-4723 and miRNA-149, which we found differentially expressed in AD and NDAN vs. control. We thus hypothesized that these miRNAs play an important role in promoting either synaptic resistance or sensitization to Aβ oligomer binding. Using an in vivo mouse model, we found that administration of these miRNAs affected key synaptic genes and significantly decreased Aβ binding to the synapses. Our findings suggest that miRNA regulation and homeostasis are crucial for Aβ interaction with synaptic terminals and support that a unique miRNA regulation could be driving synaptic resistance to Aβ toxicity in NDAN, thus contributing to their preserved cognitive abilities.

Citing Articles

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References

Vandenberghe R . The relationship between amyloid deposition, neurodegeneration, and cognitive decline in dementia. Curr Neurol Neurosci Rep. 2014; 14(11):498. DOI: 10.1007/s11910-014-0498-9. View

Selkoe D . Alzheimer's disease is a synaptic failure. Science. 2002; 298(5594):789-91. DOI: 10.1126/science.1074069. View

Yaari R, Corey-Bloom J . Alzheimer's disease. Semin Neurol. 2007; 27(1):32-41. DOI: 10.1055/s-2006-956753. View

Henstridge C, Pickett E, Spires-Jones T . Synaptic pathology: A shared mechanism in neurological disease. Ageing Res Rev. 2016; 28:72-84. DOI: 10.1016/j.arr.2016.04.005. View

Sengupta U, Nilson A, Kayed R . The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMedicine. 2016; 6:42-49. PMC: 4856795. DOI: 10.1016/j.ebiom.2016.03.035. View

Reese L, Laezza F, Woltjer R, Taglialatela G . Dysregulated phosphorylation of Ca(2+) /calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer's disease. J Neurochem. 2011; 119(4):791-804. PMC: 4021864. DOI: 10.1111/j.1471-4159.2011.07447.x. View

Aisenbrey C, Borowik T, Bystrom R, Bokvist M, Lindstrom F, Misiak H . How is protein aggregation in amyloidogenic diseases modulated by biological membranes?. Eur Biophys J. 2007; 37(3):247-55. DOI: 10.1007/s00249-007-0237-0. View

Aizenstein H, Nebes R, Saxton J, Price J, Mathis C, Tsopelas N . Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008; 65(11):1509-17. PMC: 2636844. DOI: 10.1001/archneur.65.11.1509. View

Gomez-Isla T, HOLLISTER R, West H, Mui S, Growdon J, Petersen R . Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997; 41(1):17-24. DOI: 10.1002/ana.410410106. View

10.

Karran E, Mercken M, De Strooper B . The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011; 10(9):698-712. DOI: 10.1038/nrd3505. View

11.

Maarouf C, Daugs I, Kokjohn T, Walker D, Hunter J, Kruchowsky J . Alzheimer's disease and non-demented high pathology control nonagenarians: comparing and contrasting the biochemistry of cognitively successful aging. PLoS One. 2011; 6(11):e27291. PMC: 3210154. DOI: 10.1371/journal.pone.0027291. View

12.

Zolochevska O, Bjorklund N, Woltjer R, Wiktorowicz J, Taglialatela G . Postsynaptic Proteome of Non-Demented Individuals with Alzheimer's Disease Neuropathology. J Alzheimers Dis. 2018; 65(2):659-682. PMC: 6130411. DOI: 10.3233/JAD-180179. View

13.

Bjorklund N, Reese L, Sadagoparamanujam V, Ghirardi V, Woltjer R, Taglialatela G . Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer's disease neuropathology. Mol Neurodegener. 2012; 7:23. PMC: 3403985. DOI: 10.1186/1750-1326-7-23. View

14.

Dineley K, Kayed R, Neugebauer V, Fu Y, Zhang W, Reese L . Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice. J Neurosci Res. 2010; 88(13):2923-32. PMC: 2919647. DOI: 10.1002/jnr.22445. View

15.

Franklin W, Taglialatela G . A method to determine insulin responsiveness in synaptosomes isolated from frozen brain tissue. J Neurosci Methods. 2016; 261:128-34. PMC: 4749422. DOI: 10.1016/j.jneumeth.2016.01.006. View

16.

Reese L, Zhang W, Dineley K, Kayed R, Taglialatela G . Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. Aging Cell. 2008; 7(6):824-35. PMC: 2954114. DOI: 10.1111/j.1474-9726.2008.00434.x. View

17.

Dobin A, Davis C, Schlesinger F, Drenkow J, Zaleski C, Jha S . STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2012; 29(1):15-21. PMC: 3530905. DOI: 10.1093/bioinformatics/bts635. View

18.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

19.

Wang F, Ma Y, Zhang P, Shen T, Shi C, Yang Y . SP1 mediates the link between methylation of the tumour suppressor miR-149 and outcome in colorectal cancer. J Pathol. 2012; 229(1):12-24. DOI: 10.1002/path.4078. View

20.

Pevida M, Lastra A, Hidalgo A, Baamonde A, Menendez L . Spinal CCL2 and microglial activation are involved in paclitaxel-evoked cold hyperalgesia. Brain Res Bull. 2013; 95:21-7. DOI: 10.1016/j.brainresbull.2013.03.005. View