micrornas and alzheimer’s disease · alzheimer’s disease clinical-pathological studies. 3....
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MicroRNAs and
Alzheimer’s Disease
Pete Nelson
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1. MicroRNA (miRNA) biology: Overview
2. Alzheimer’s disease clinical-pathological studies
3. MiRNAs in neurodegenerative diseasesA. Technical considerationsB. Work in Alzheimer’s disease
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Epigenetic mechanismshave special relevanceto human CNS
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Epigenetic mechanismshave special relevanceto human CNS
CNS epigenetics may differ from the (cancer-relevant) “classic” epigenetic mechanisms
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~30,000 protein-coding genes
~100,000,000,000,000 synapses
(for every gene, > 1 billion synapses!)
x ~10,000
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~30,000 protein-coding genes
~100,000,000,000,000 synapses
GENETICCOMPLEXITY
MULTIPLIERS
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J. LeROY CONEL, Postnatal development of the human cerebral cortex (Volume VIII) 1967
Human neurons have special need for localized control of mRNA translation and exquisite sensitivity to the local micro-environments distal to the cell body
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mRNA
Polypetide
Ribosome,Proteins,
& non-coding RNAs
Gene expression regulation:
mRNA is ~5% of total cellular RNA and is poorly correlated with protein levels
It is increasingly clear that mRNA translation isa key focal point of gene expression regulation
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microRNAs (miRNAs)•Small noncoding RNAs (~22 nucleotides)
•Regulate mRNA translation of many/most genes
•Serve many functions in human CNS
•Increase genetic complexity and localizedcontrol of mRNA translation
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MicroRNAs (miRNAs)are short, “non
coding” RNAs thatfunction by binding toeffector proteins and
guiding those proteinsto mRNA “targets”
Nelson P et al, Trends Bioch Sci, 2003
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Nelson P et al, Trends Bioch Sci, 2003
THERAPEUTICPOTENTIAL:a “loaded allele-killer”
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miRNA biology holds promisefor therapeutic interventions
Huntingtin knock-down in Rhesus monkeys usinginfusions of siRNA typeagent into the striatum
Much thanks to Dr. Don Gash(Alnylam & Medtronic)
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1. MicroRNA (miRNA) biology: BRIEF overview
2. Alzheimer’s disease: clinical-pathological correlation
3. MiRNAs in neurodegenerative diseasesA. Technical considerationsB. Work in Alzheimer’s disease
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Do miRNAs play a role inAlzheimer’s disease ?
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What is Alzheimer’s disease ?
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What is Alzheimer’s disease ?
Cognitive impairment
Neocortical neurofibrillary tangles
Neocortical neuritic amyloid plaques
Clinical
Pathological
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NEUROFIBRILLARY TANGLE NEURITIC AMYLOID PLAQUE
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PlaquesCognitiveImpairmentTangles
Clinicopathological studies are compatible with the hypothesisthat plaques and tangles contribute to cognitive impairment
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1. MicroRNA (miRNA) biology: Overview
2. Alzheimer’s disease biology
3. MiRNAs in neurodegenerative diseasesA. Technical considerationsB. Work in Alzheimer’s disease
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Studying miRNAs in human brain disease: technical notes
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Experimental paradigm:
“Control” “Alzheimer’s disease”
Tissue-level miRNA profiling
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Control cerebral cortex End-stage AD cerebral cortex
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“Gray Matter”; mostly:-Neurons-Astrocytes-Rich vascular
“White Matter”; mostly:-Oligodendrocytes-Astrocytes-Lacks Neurons
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Acta Neuropathologica, 2011
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Experimental paradigm:
Tissue-level miRNA profiling
Should be complemented bycellular-level miRNA profiling
MiRNA in situ hybridization
RNA, 2006
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1. MicroRNA (miRNA) biology: Overview
2. Alzheimer’s disease biology
3. MiRNAs in neurodegenerative diseasesA. Technical considerationsB. Work in Alzheimer’s disease
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Our Lab’s Overall Goal:Identify all miRNA targets in human brain across a range of pathologies
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Our Lab’s Overall Goal:Identify all miRNA targets in human brain across a range of pathologies
My Goal for next 8 minutes:Convince you that this is a worthygoal by demonstrating an exampleof a miRNA “story” relevant to AD.
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miR-107is a miRNA that we found to bedown-regulatedearly in AD pathogenesis
J Neuroscience, 2008
J Alzheimer’s Disease, 2010
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Outside validation:Human study
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Outside validation:Transgenic mice
study
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J Mol Biol, 2010Acta Neuropathol 2011
miR-15/107 gene group:
Expressed in all human cells
Similar 5’ seed motif--dictates activity
5 different highly-expressed miRNAs downregulated in AD gray matter: strong potential amplification effect
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Because of the studies in human brains,we wanted to know the targets of miR-107
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miR-107 regulates bothGRN/PGRN and BACE1
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BACE1:Beta-site amyloid precursor protein cleaving enzyme 1
W-X Wang et al, J Neurosci 2008
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BACE
α-secretase
γ-secretase
β-amyloid precursor protein
membrane
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BACE
γ-secretase
β-amyloid precursor protein
membrane
Aβ (1-40,42)
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Thioflavin stain (Amyloid pathology)Brain section from patient with Alzheimer’s disease
Aβ (1-40,42)
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BACE1:
Beta-site amyloid precursor protein cleaving enzyme 1
Cleaves APP to produce toxic Abeta(1-40) and/or Abeta(1-42) peptides
Important point:
BACE1 -- GOOD
BACE1 -- BAD
Ohno, M., E.A. Sametsky, L.H. Younkin, H. Oakley, S.G. Younkin, M. Citron, R. Vassar, and J.F. Disterhoft, BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron, 2004. 41(1): p. 27-33.
Marambaud, P., N. Chevallier, K. Ancolio, and F. Checler, Post-transcriptional contribution of a cAMP-dependent pathway to the formation of alpha- and beta/gamma-secretases-derived products of beta APP maturation in human cells expressing wild-type and Swedish mutated beta APP. Mol Med, 1998. 4(11): p. 715-23.
Rossner, S., M. Sastre, K. Bourne, and S.F. Lichtenthaler, Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease. Prog Neurobiol, 2006. 79(2): p. 95-111.
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Am J Pathol, 2010
GRN/PGRN wasidentified as miR-107target using unbiasedhigh-throughputscreening method
GRN was by far thestrongest targetfor miR-107 usingthis technique
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GRN/Granulin
aka
Progranulin (PGRN)AcrograninGlycoprotein 88kDa (Gp88)ProepithelinPC cell-derived growth factor (PCDGF)Epithelial transforming growth factor (TGFe)Granulin-epithelin precursor (GEP)
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GRN/Granulin
Strong growth factorInflammationWound repairNeoplasia
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GRN/Granulin
Frontotemporal dementia
haploinsufficiency
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Is there a plausible hypothesis to explain
significance ofmiR-107 decrease in AD
brains?
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Is there a plausible hypothesis to explain
significance ofmiR-107 decrease in AD
brains?
3 Clues
1. Genomics2. Glucose (Tang et al, Sabire Ozcan Lab)3. Brain Trauma (Redell et al, Pramod Dash Lab)
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Young (20-39 y.o.) ApoE4 carriers at geneticrisk for developing ADshow decreased glucosemetabolism in a patternreminiscent of AD brains
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MiR-107 gene(s) are located within introns of PANK gene in all vertebrates
PANK is the universal, rate-determining enzyme in CoA formation
PANK is regulated transcriptionally in response to metabolic requirements
MiR-107 is predicted to participate in metabolic pathways in synchronywith PANK function
May link metabolic and pathologic pathways in Alzheimer’s disease
From Wilfred B et al, Mol Genet Metab. 2007
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Sabire Ozcan’s lab
Pancreatic beta-cell line
Glucose miR-107 expression
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High glucose Increased miR-107Decreased GRN
Am J Pathol, 2010
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Traumatic brain injury
Ipsilateral side: -Decreased miR-107-Increased GRN/PGRN
Compatible with hypothesisthat miR-107 regulates GRN/PGRNand this is relevant to neural injury
Thanks to Dr. Kathy Saatman and Dr. Sindhu Kizhakke
Am J Pathol, 2010
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Glucose
miR-107
GRN/PGRNBACE1
Modulation of metabolismand/or neuroinflammation
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Glucose
miR-107
GRN/PGRNBACE1
Modulation of metabolismand/or neuroinflammation
Brain injury
Alzheimer’s disease?
BACE1
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Summary
1.mRNA translation is key node of gene expression regulation
2.miRNAs are a key regulator of translation
3.In miRNA profiling, technical details are important
4.miRNA expression is systematically altered in AD
5.miRNAs dysregulated in AD impact genes implicated in AD and FTLD
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WE HAVE ONLYBEGUN TO SCRATCH THE SURFACE OFmicroRNA BIOLOGY IN HUMAN BRAIN
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Lab
NeuropathologyCore
UK ADC
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Erin Abner, MPH
Fred Schmitt, PhD
Dick Kryscio, PhD
Greg Jicha, MD PhD
Linda Van Eldik, PhD
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Thanks
Dr. Zissimos Mourelatos
Dr. William Markesbery
NIH/NIA R21 Grant
NIH/NINDS RO1 Grant
NIH/NIA P30 Grant
http://www.mc.uky.edu/coa/faculty/nelson.html