microRNA in Alzheimer’s disease and Depression

I International Symposium: Neurobiology and Biomarkers of Brain Aging

Ana Paula Mendes SilvaPhD Student

Federal University of Minas Gerais/UFMG

miRNA

Biomarkers

CharacteristicsAdvantages and

limitations

Major depressive disorder

Alzheimer’s disease

Gene therapy

http://www.mdpi.com/2075-4418/3/1/84/htm

• Non-coding RNA

CharacteristicsCharacteristics

http://mcb.berkeley.edu/labs/he/Research.htm

miRNA

• microRNAs mediate translational repression or mRNA degradation

Post-transcriptional regulators of gene expression

18 to 22-nucleotides-long

• Horizontal transfer of miRNAs by secreted extracellular vesicles -> intercellular communication

CharacteristicsCharacteristics

http://circres.ahajournals.org/content/110/3/483.abstract

• A single miRNAs can target multiple mRNAs

CharacteristicsCharacteristics

hsa-miR-664

SLC10A2

ARID1A

PKN2

COPG

ZNF423 GPHN

IRF2

STRAP

ARID1B

CPEB4

KCMF1

ADCYAP1MDGA2

KLF12

AHCTF1PAHCTF1

FRMPD4

RSBN1

FAM7A3 BHLHB9

FAM7A1

ZMYND11

CT47A9

SMYD1

TTC33

RBM26

• Multiple miRNAs can target a single mRNA

CharacteristicsCharacteristics

BDNF

hsa-miR-1

hsa-miR-206

hsa-miR-613

hsa-miR-374b hsa-miR-495

hsa-miR-374a

hsa-miR-10a

hsa-miR-195

hsa-miR-216b

hsa-miR-122

hsa-miR-30a

hsa-miR-30e

BiomarkerBiomarker

• A biomarker is an indicator of physiological, biochemical, or anatomic parameter

Biological Biological ProcessesProcesses

Pathological Pathological ProcessesProcesses

Therapeutic Therapeutic InterventionIntervention

BiomarkerBiomarker

• miRNAs can be detected in serum, plasma, urine, and other biological fluids

Body fluidsBody fluids

http://www.mirnabodymap.org/

AdvantagesAdvantages

• Horizontal transfer

• Mature miRNAs are small

• Stable molecules

• Resistant to RNA degradation

• Highly conserved among species

• Differentiate pathological phenotypes

• Provide global disease profiling

• Customized treatment:

– Rational drug selection

– Monitoring response to therapy

• Alows risk stratification

AdvantagesAdvantages

• Noninvasive biomarkers

• Positive impact in patient comfort

• Can lead to early diagnosis

• Might enable patients to get on treatments earlier, preventing the devastanting effects of the disease

AdvantagesAdvantages

LimitationsLimitations

• It’s difficult to measure each miRNA contribuition to the disease

• The presence of miRNAs in collected fluids does not directly indicate the inhibition of the translation process

• Although a single miRNA can be related with multiple pathologies it does not necessarily mean that all the pathologies will develop

• Cost of miRNA sequencing

Meta-analysisMeta-analysisId

enti

ficat

ion Records identified through Web of

Science

Scre

enin

gIn

clud

edEl

igib

ility

Records identified through PubMed

Records after duplicates removed

Records screened

Records excluded, because they are reviews, book chapters,

meeting abstracts, descriptive articles and protocoll papers

Full-text articles accessed for eligibility

Full-text articles excluded, miRNAs specific cell, animal

models and the blood of patients under the use of any

medication

Studies included in the analysis

Records identified through SCOPUS

http://www.prisma-statement.org/

6 AD 3 D

416 AD 176 D

Alzheimer’s diseaseAlzheimer’s disease• The words used to identify the miRNAs related to

Alzheimer’s were: Alzheimer’s disease and miRNA.

• Identified 77 miRNAs differently expressed

miRNAs searchmiRNAs search

NetworkNetwork

447 genes

Major depressive disorderMajor depressive disorder

• The words used to identify the miRNAs related to depression were: (Major depressive disorder OR depressive disorder OR depression) and miRNA.

• Identified 32 miRNAs differently expressed

NetworkNetwork

210 genes

MiRNAs common to Alzheimer’s disease and MiRNAs common to Alzheimer’s disease and depressiondepression

hsa-miR-26b

hsa-miR-664

hsa-let-7d

hsa-let-7g

hsa-let-7fhsa-miR-191

hsa-miR-30d hsa-miR-361-5p

155 genes155 genes

5418

5467

5544

7467

6114

2015

8089

5616

NetworkNetwork

• Up-regulated – AntagomiRs are used to decrease the levels of

specific miRNA

• Down-regulated– Synthetic RNAs or siRNAs are used to increase the

levels

Gene therapyGene therapy

Gene therapyGene therapy

miRNAs Regulation FoldChange

hsa-miR-766-3p Down-regulated 9,54

hsa-miR-26b-5p Down-regulated 8,58

hsa-miR-340-5p Up-regulated 7,61

hsa-miR-6509-5p Up-regulated 7,43

cel-miR-39 Baseline (endogenous) _____________

Genome-wide sérum microRNA expression. Profiling identifies sérum biomarkers for Alzheimer’s disease. Tan, L.; Yu,J.T.; Tan, M.S.; Liu, Q.Y.; Wang, H.F.; Zhang, W.; Jiang, T. and Tan.L. Journal of Alzheimer’s disease 40 (2014) 1017-1027.

Thank You for your atention!Thank You for your atention!

e-mail: apmendes@ufmg.br