microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain

Kim, Jaekwang; Yoon, Hyejin; Horie, Takahiro; Burchett, Jack M.; Restivo, Jessica L.; Rotllan, Noemi; Ramírez, Cristina M.; Verghese, Philip B.; Ihara, Masafumi; Hoe, Hyang-Sook; Esau, Christine; Fernández-Hernando, Carlos; Holtzman, David M.; Cirrito, John R.; Ono, Koh; Kim, Jungsu

doi:10.1523/jneurosci.2053-15.2015

Cited by 128Alzheimer's disease research and treatmentsMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain

Open access

Kim, Jaekwang, Yoon, Hyejin, Horie, Takahiro, Burchett, Jack M., Restivo, Jessica L., Rotllan, Noemi, Ramírez, Cristina M., Verghese, Philip B. +8 more·2015·The Journal of Neuroscience

DOI 10.1523/jneurosci.2053-15.2015PMC PMC4635126

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Abstract

Dysregulation of amyloid-β (Aβ) metabolism is critical for Alzheimer's disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in Aβ metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects Aβ levels. Therefore, identifying regulatory mechanisms of ABCA1 expression in the brain may provide new therapeutic targets for AD. Here, we demonstrate that microRNA-33 (miR-33) regulates ABCA1 and Aβ levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular Aβ levels by promoting Aβ secretion and impairing Aβ clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous Aβ levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased Aβ levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD. SIGNIFICANCE STATEMENT Brain lipid metabolism, in particular Apolipoprotein E (ApoE) lipidation, is critical to Aβ metabolism and Alzheimer's disease (AD). Brain lipid metabolism is largely separated from the periphery due to blood–brain barrier and different repertoire of lipoproteins. Therefore, identifying the novel regulatory mechanism of brain lipid metabolism may provide a new therapeutic strategy for AD. Although there have been studies on brain lipid metabolism, its regulation, in particular by microRNAs, is relatively unknown. Here, we demonstrate that inhibition of microRNA-33 increases lipidation of brain ApoE and reduces Aβ levels by inducing ABCA1. We provide a unique approach for AD therapeutics to increase ApoE lipidation and reduce Aβ levels via pharmacological inhibition of microRNA in vivo.

AI snapshot

Written from the paper’s full text.

TL;DR

miR-33 is enriched in the brain, directly suppresses ABCA1, and regulates ApoE lipidation and Aβ metabolism in neural cells. Genetic deletion or brain-specific antisense inhibition of miR-33 increases ABCA1/ApoE lipidation and lowers cortical Aβ in mice, suggesting a potential AD therapeutic strategy.

Key findings

miR-33 is highly enriched in brain and expressed in neurons, astrocytes, and microglia, with relatively higher expression in neurons.
miR-33 directly targets the ABCA1 3′UTR; overexpression suppressed ABCA1 in N2a cells and primary astrocytes, while mir-33 deletion increased cortical ABCA1.
miR-33 overexpression impaired ApoE-mediated cholesterol efflux, increased CTFβ and secreted Aβ, and impaired Aβ clearance/degradation; miR-33-resistant Abca1 ORF rescued these effects.
mir-33 deletion increased ApoE lipidation and decreased endogenous cortical Aβ40 by 33% and Aβ42 by 40%; brain-specific anti-miR-33 in APP/PS1 mice significantly decreased Aβ40 (p = 0.0286) and showed a trend for Aβ42 (p = 0.0954, 24% difference between means).

Methods

In vitro studies used mouse N2a, human H4-APPsw neuroglioma cells, and mouse primary astrocytes, with luciferase reporter assays, cholesterol efflux assays, Aβ secretion/clearance/degradation assays, qRT-PCR, and Western blotting.
In vivo studies used mir-33 knockout mice and 2-month-old APP/PS1 transgenic mice treated with 30 µg/d anti-miR-33 or mismatch control for 4 weeks via intracerebroventricular infusion using osmotic pumps; female mice were used.
Cortical Aβ was measured by sandwich ELISA and normalized to total protein; ApoE lipidation was assessed by native PAGE/Western blot; statistical testing used two-tailed Student’s t test after variance/normality checks, with two-way ANOVA for degradation assays.

Limitations

The paper states that no human clinical trial has demonstrated that an antisense oligonucleotide can reduce a target RNA or protein in the brain, and that blood-brain barrier delivery remains a major obstacle for clinical application.
The paper notes that miRNA overexpression may produce artificial effects by surpassing biological buffering capacity, making endogenous modulation important; the study addresses this with knockout and brain-specific inhibition.
Evident from the text: most mechanistic work is in cell lines and mice, with no behavioral/cognitive outcomes reported; anti-miR-33 reduced Aβ42 only as a trend; and all in vivo experiments used female mice, with small sample sizes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1523/jneurosci.2053-15.2015

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

20 of 48 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured

Premisecitation
Alterations in ApoE protein levels and lipidation status strongly influence Aβ metabolism.
“and lipidation status have been shown to strongly influence A␤ metabolism (Kim et al., 2009a,b;Bien-Ly et al., 2012).”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Kim et al., 2009a,b
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Bien-Ly et al., 2012 source
  The Results section, “Halving the levels of apoE significantly attenuates Aβ accumulation in aged mice” (page unavailable), reports that reducing apoE3 or apoE4 levels reduced Aβ accumulation in aged mice. The copy does not establish that apoE lipidation status influences Aβ metabolism; its Discussion mentions other lipid-metabolism processes only as a possible explanation requiring further study. (LLM, conf=0.88)
  Experimental — accuracy not yet measured
Premisecitation
Dysregulation of cholesterol metabolism is implicated in AD pathogenesis.
“Mounting evidence has demonstrated that dysregulation of cholesterol metabolism is implicated in AD pathogenesis (Kim et al., 2009a;Di Paolo and Kim, 2011).”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Kim et al., 2009a
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Di Paolo and Kim, 2011 source
Premisecitation
ABCA1 decreases Aβ levels by promoting extracellular Aβ clearance in both neurons and glial cells.
“In addition to its role in A␤ secretion, ABCA1 has been also shown to decrease A␤ levels by promoting extracellular A␤ clearance in both neurons and glial cells (Jiang et al., 2008;Kim et al., 2012).”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Jiang et al., 2008 source
- cites Kim et al., 2012 source
  The Results section ('Impairment of Aβ clearance by miR-106b is rescued by ABCA1 ORF expression'; page unavailable) reports that restoring ABCA1 rescued impaired extracellular Aβ clearance in neuronal cells. The Discussion says ABCA1 overexpression did not increase clearance above baseline in those cells and only suggests a possible clearance mechanism in microglia. The claim therefore overstates the evidence for promoted clearance in both neurons and glial cells. (LLM, conf=0.89)
  Experimental — accuracy not yet measured
Premisecitation
ABCA1 decreases Aβ secretion by inhibiting BACE1-mediated APP cleavage without affecting BACE1 expression in neuronal cells.
“We and others previously demonstrated that ABCA1 decreases A␤ secretion by inhibiting BACE1-mediated APP cleavage without affecting BACE1 expression in neuronal cells (Sun et al., 2003;Kim et al., 2012).”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Sun et al., 2003 source
- cites Kim et al., 2012 source
Premisecitation
In vitro evidence supports a critical role of ABCA1 in Aβ production.
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A␤ production, although how ABCA1 regulates A␤ production remains to be clarified (Koldamova et al., 2003;Sun et al., 2003;Kim et al., 2007).”
Quote in the paperSubstantial claim2 of 3 sources checked
- cites Koldamova et al., 2003 source
  The Abstract (page unavailable) reports decreased Aβ production in cultured cells after LXR/RXR ligand treatment, with or without ABCA1-mediated cholesterol depletion. The Discussion (page unavailable) says ABCA1 may affect APP processing and Aβ secretion, but also says the ligand effects might depend on factors beyond ABCA1. This supports a possible role, not the stronger claim that this study establishes a critical role for ABCA1. (LLM, conf=0.85)
  Experimental — accuracy not yet measured
- cites Sun et al., 2003 source
- cites Kim et al., 2007 source

Premisecitation
ApoE lipidation by ABCA1 is critical for Aβ clearance.
“ApoE lipidation by ABCA1 is critical for A␤ clearance (Jiang et al., 2008;Kim et al., 2012).”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Jiang et al., 2008 source
- cites Kim et al., 2012 source
  The Discussion reports that fully lipidated apoE is required for effective Aβ degradation in microglia and that reducing ABCA1 impaired extracellular Aβ clearance. But it says ABCA1 *may* affect clearance by facilitating apoE lipidation and that the mechanism remains unclear; it does not establish that this route is critical. (LLM, conf=0.86)
  Experimental — accuracy not yet measured
Premisecitation
Intrathecal ASO injection to nonhuman primates led to accumulation of ASO in the cortical neuronal and glial cells.
“intrathecal ASO injection to nonhuman primates led to accumulation of ASO in the cortical neuronal and glial cells (Rigo et al., 2014).”
Quote in the paperNot a substantial claim1 of 1 sources checked
- cites Rigo et al., 2014 source
Premisecitation
ABCA1 is required for the effective clearance of Aβ by neuronal and glial cells.
“we and others have shown that ABCA1 is required for the effective clearance of A␤ by neuronal and glial cells”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Jiang et al., 2008 source
- cites Kim et al., 2012 source
  The Results section ('Impairment of Aβ clearance by miR-106b is rescued by ABCA1 ORF expression'; page not provided) shows that restoring ABCA1 rescued impaired Aβ clearance in neuronal cells, but only when the medium contained FBS. The Discussion (page not provided) describes ABCA1's possible role in microglial clearance as a suggestion, not an established requirement. The claim therefore extends the neuronal-cell finding to glial cells and omits the experimental condition. (LLM, conf=0.88)
  Experimental — accuracy not yet measured
Findingown data
mir-33 gene deletion decreases endogenous Aβ42 levels by 40% in cortex.
“mir-33 gene deletion markedly increased ABCA1 levels (Fig. 7 A, B) and decreased endogenous A␤ 40 levels by 33% and A␤ 42 levels by 40% in cortex (Fig. 7C,D).”
Quote in the paperSubstantial claim
Findingown data
mir-33 deletion significantly facilitates extracellular Aβ degradation compared with WT.
“We found that mir-33 deletion significantly facilitated extracellular A␤ degradation, compared with WT (Fig. 6C,D).”
Quote in the paperSubstantial claim
Findingown data
miR-33 increases intracellular CTFβ levels in N2a-APPsw cells.
“miR-33 markedly decreased ABCA1 levels and increased the levels of intracellular CTF␤, the cleavage product of APP by BACE1, and the secreted A␤ (Fig. 4A,B).”
Quote in the paperSubstantial claim
Findingown data
Anti-miR-33 therapy shows a trend of decreasing Aβ42 levels (24% difference between means) in cortex.
“There was also a trend showing that anti-miR-33 decreased A␤ 42 levels (24% difference between means) (Fig. 8D).”
Quote in the paperSubstantial claim
Findingown data
miR-33 markedly decreases ABCA1 levels in N2a-APPsw cells.
“miR-33 markedly decreased ABCA1 levels and increased the levels of intracellular CTF␤, the cleavage product of APP by BACE1, and the secreted A␤ (Fig. 4A,B).”
Quote in the paperSubstantial claim
Findingown data
Anti-miR-33 significantly decreases CTFβ levels in cortex compared with mismatch control.
“Anti-miR-33 significantly increased ABCA1 protein levels and decreased CTF␤ levels in cortex, compared with the mismatch control (Fig. 8 A, B).”
Quote in the paperSubstantial claim
Findingown data
In the presence of miR-33-resistant Abca1 without 3'UTR, miR-33 does not affect ABCA1 levels nor Aβ levels in N2a cells expressing APPsw.
“In the presence of miR-33 resistant Abca1 without 3ЈUTR (Abca1 ORF), miR-33 did not affect ABCA1 levels nor A␤ levels in N2a cells expressing APPsw, suggesting that miR-33 regulates A␤ secretion via modulating ABCA1, rather than other genes (Fig. 4E,F).”
Quote in the paperSubstantial claim
Findingown data
miR-33 increases secreted Aβ levels in N2a-APPsw cells.
“miR-33 markedly decreased ABCA1 levels and increased the levels of intracellular CTF␤, the cleavage product of APP by BACE1, and the secreted A␤ (Fig. 4A,B).”
Quote in the paperSubstantial claim
Findingown data
miR-33 dramatically impairs Aβ clearance in N2a, H4, and mouse primary astrocytes.
“We found that miR-33 dramatically impaired A␤ clearance in N2a, H4, and mouse primary astrocytes (Fig. 5 A, B).”
Quote in the paperSubstantial claim
Findingown data
Overexpression of miR-33 significantly impairs Aβ degradation in astrocyte conditioned media.
“Overexpression of miR-33 significantly impaired A␤ degradation in the astrocyte conditioned media (Fig. 6 A, B).”
Quote in the paperSubstantial claim
Findingown data
miR-33 overexpression significantly suppresses ABCA1 expression in N2a cells and astrocytes.
“miR-33 overexpression significantly suppressed ABCA1 expres-sion in both cell types (Fig. 2C,D).”
Quote in the paperSubstantial claim
Findingown data
miR-33 does not affect BACE1 levels in N2a-APPsw cells.
“As expected from previous ABCA1 studies (Sun et al., 2003;Kim et al., 2012), miR-33 did not affect the levels of BACE1 (Ctl 100.0 Ϯ 1.774 vs miR-33 101.0 Ϯ 3.652, n ϭ 5, p ϭ 0.8061).”
Quote in the paperSubstantial claim
Findingown data
ApoE-containing lipoprotein particles from mir-33-deficient mice tend to be larger in size than particles from WT mice.
“ApoE-containing lipoprotein particles from the mir-33-deficient mice tended to be larger in size than the particles from WT mice, indicating that inhibition of miR-33 increases ApoE lipidation in the brain (Fig. 3B).”
Quote in the paperSubstantial claim
Findingown data
miR-33 suppresses luciferase activity in N2a cells.
“miR-33 suppressed the luciferase activity, whereas LNA-based miR-33 inhibitor (referred to miR-33-I) increased luciferase expression in N2a cells (Fig. 2B).”
Quote in the paperSubstantial claim
Findingown data
miR-33 is highly enriched in the brain.
“Interestingly, miR-33 is highly enriched in the brain (Fig. 1A) and is widely expressed across multiple brain regions (Fig. 1B).”
Quote in the paperSubstantial claim
Findingown data
mir-33 gene deletion decreases endogenous Aβ40 levels by 33% in cortex.
“mir-33 gene deletion markedly increased ABCA1 levels (Fig. 7 A, B) and decreased endogenous A␤ 40 levels by 33% and A␤ 42 levels by 40% in cortex (Fig. 7C,D).”
Quote in the paperSubstantial claim
Findingown data
Expression of miR-33-resistant Abca1 ORF completely restores the miR-33-mediated reduction of Aβ clearance in mouse primary astrocytes.
“Moreover, expression of miR-33resistant Abca1 ORF completely restored the miR-33-mediated reduction of A␤ clearance in mouse primary astrocytes (Fig. 5C,D).”
Quote in the paperSubstantial claim
Findingown data
miR-33 significantly decreases ApoE-mediated cholesterol efflux in N2a cells and astrocytes.
“miR-33 significantly decreased ApoE-mediated cholesterol efflux in both N2a cells and astrocytes (Fig. 3A).”
Quote in the paperSubstantial claim
Findingown data
Anti-miR-33 therapy significantly decreases Aβ40 levels in cortex.
“Importantly, anti-miR-33 therapy significantly decreased A␤ 40 levels in cortex (Fig. 8C).”
Quote in the paperSubstantial claim
Findingown data
mir-33 gene deletion markedly increases ABCA1 levels in cortex.
“mir-33 gene deletion markedly increased ABCA1 levels (Fig. 7 A, B) and decreased endogenous A␤ 40 levels by 33% and A␤ 42 levels by 40% in cortex (Fig. 7C,D).”
Quote in the paperSubstantial claim
Findingown data
miR-33 effectively suppresses ABCA1 in the brain.
“In our current study, we demonstrated that miR-33 effectively suppresses ABCA1 in the brain.”
- Also stated in: § Discussion · boosted
  “Here, we clearly demonstrated that endogenous miR-33 suppresses ABCA1 expression under basal condition by using mir-33-deficient mice as well as inhibiting endogenous miR-33 specifically in the brain.”
- Also stated in: § Discussion · plain
  “Figure 2. miR-33 suppresses ABCA1 expression in the brain.”
Quote in the paperSubstantial claim
Findingown data
LNA-based miR-33 inhibitor increases luciferase expression in N2a cells.
“miR-33 suppressed the luciferase activity, whereas LNA-based miR-33 inhibitor (referred to miR-33-I) increased luciferase expression in N2a cells (Fig. 2B).”
Quote in the paperSubstantial claim
Findingown data
Anti-miR-33 significantly increases ABCA1 protein levels in cortex compared with mismatch control.
“Anti-miR-33 significantly increased ABCA1 protein levels and decreased CTF␤ levels in cortex, compared with the mismatch control (Fig. 8 A, B).”
Quote in the paperSubstantial claim
Findingown data
ABCA1 protein levels are strongly increased in cortex of mir-33-deficient mice compared with WT mice.
“Importantly, ABCA1 protein levels were strongly increased in cortex of mir-33-deficient mice (miR-33 (Ϫ/Ϫ)), compared with WT mice (miR-33 (ϩ/ϩ)) (Fig. 2 F, G)”
Quote in the paperSubstantial claim
Findingown data
mir-33-deficient mice have significantly less PBS-soluble ApoE levels in cortex compared with WT mice.
“Moreover, mir-33deficient mice had significantly less PBS-soluble ApoE levels in cortex, compared with WT mice (Fig. 3C,D).”
Quote in the paperSubstantial claim
Findingown data
miR-33 is widely expressed across multiple brain regions.
“Interestingly, miR-33 is highly enriched in the brain (Fig. 1A) and is widely expressed across multiple brain regions (Fig. 1B).”
Quote in the paperNot a substantial claim
Findingown data
mir-33 deletion increased highly lipidated ApoE-containing particles.
“mir-33 deletion increased highly lipidated ApoE-containing particles.”
Quote in the paperSubstantial claim
Findingown data
miR-33 directly targets the 3'UTR of ABCA1 mRNA.
“miR-33 directly targets the 3ЈUTR of ABCA1 mRNA.”
Quote in the paperSubstantial claim
Findingown data
Overexpression of miR-33 impairs Aβ clearance in neural cells.
“Figure 5. Overexpression of miR-33 impairs A␤ clearance in neural cells.”
Quote in the paperSubstantial claim
Findingnone given
The roles of miR-33 in Aβ metabolism are conserved in mouse and human neural cells.
“We also demonstrated that the roles of miR-33 in A␤ metabolism are conserved in mouse and human neural cells.”
Quote in the paperSubstantial claim
Findingown data
Overexpression of miR-33 increases Aβ secretion by suppressing ABCA1 in neural cells.
“Figure 4. Overexpression of miR-33 increases A␤ secretion by suppressing ABCA1 in neural cells.”
Quote in the paperSubstantial claim
Findingown data
Inhibition of miR-33 in the brain significantly decreased β-cleavage of APP in APP/PS1 mice.
“inhibition of miR-33 in the brain significantly decreased ␤-cleavage of APP in APP/PS1 mice.”
Quote in the paperSubstantial claim
Findingown data
Brain-specific miR-33 inhibition decreases Aβ levels in cortex of APP/PS1 mice.
“Figure 8. Brain-specific miR-33 inhibition decreases A␤ levels in cortex of APP/PS1 mice.”
Quote in the paperSubstantial claim
Findingown data
mir-33 deletion decreases mouse endogenous Aβ levels in cortex.
“Figure 7. mir-33 deletion decreases mouse endogenous A␤ levels in cortex.”
Quote in the paperSubstantial claim
Findingown data
PBS-soluble apoE levels were decreased in mir-33-deficient mice, compared with WT.
“PBS-soluble apoE levels were decreased in mir-33-deficient mice, compared with WT.”
Quote in the paperSubstantial claim
Findingown data
Deletion of miR-33 facilitated extracellular Aβ degradation in PBS-soluble fractions of cortices.
“Deletion of miR-33 facilitated extracellular A␤ degradation in PBS-soluble fractions of cortices.”
Quote in the paperSubstantial claim
Findingown data
Anti-miR-33 markedly increased ABCA1 levels in cortex of APP/PS1 mice compared with the mismatch control.
“Anti-miR-33 markedly increased ABCA1 levels in cortex of APP/PS1 mice (n ϭ 9), compared with the mismatch control (n ϭ 6) (A, B).”
Quote in the paperSubstantial claim
Findingown data
Overexpression of miR-33 impaired extracellular Aβ degradation in the conditioned media from astrocytes.
“Overexpression of miR-33 impaired extracellular A␤ degradation in the conditioned media from astrocytes.”
Quote in the paperSubstantial claim
Findingown data
miR-33 decreased ABCA1 levels in N2a cells and mouse primary astrocytes.
“miR-33 decreased ABCA1 levels in N2a cells (n ϭ 6) and mouse primary astrocytes (n ϭ 5).”
Quote in the paperSubstantial claim
Findingown data
ASO-based pharmacological inhibition of miR-33 reduces Aβ levels in the brain after intracerebroventricular delivery of anti-miR-33 ASO.
“In the current study, we demonstrated that ASO-based pharmacological inhibition of miR-33 reduces A␤ levels in the brain after intracerebroventricular delivery of anti-miR-33 ASO.”
Quote in the paperSubstantial claim
Findingown data
The levels of Aβ40 and Aβ42 are significantly decreased in cortex of mir-33 knock-out mice compared with WT.
“The levels of A␤ 40 (C) and A␤ 42 (D) are significantly decreased in cortex of mir-33 knock-out mice (n ϭ 7), compared with WT (n ϭ 9).”
Quote in the paperSubstantial claim
Findingown data
Overexpression of miR-33 increased Aβ secretion in neuronal cells by increasing β-cleavage of APP.
“we observed that overexpression of miR-33 increased A␤ secretion in neuronal cells by increasing ␤-cleavage of APP.”
Quote in the paperSubstantial claim
Findingown data
Overexpression of Abca1 ORF restored the reduction of Aβ clearance.
“Overexpression of Abca1 ORF restored the reduction of A␤ clearance.”
Quote in the paperSubstantial claim
Findingown data
ABCA1 levels were increased in cortex of mir-33 knock-out mice compared with WT mice.
“ABCA1 levels were increased in cortex of mir-33 knock-out mice (miR-33 (Ϫ/Ϫ), n ϭ 5), compared with WT mice (miR-33 (ϩ/ϩ), n ϭ 5).”
Quote in the paperSubstantial claim
Findingown data
Overexpression of Abca1 ORF restored miR-33-mediated alteration of secreted Aβ levels.
“Overexpression of Abca1 ORF restored miR-33-mediated alteration of secreted A␤ levels.”
Quote in the paperSubstantial claim
Findingown data
miR-33 impaired cellular cholesterol efflux in N2a and astrocytes.
“miR-33 impaired cellular cholesterol efflux in N2a and astrocytes.”
Quote in the paperSubstantial claim
Study design and conductown data
The specificity of the Aβ ELISA was validated with brain tissue lysates from APP knock-out mice.
“The specificity of A␤ ELISA was validated with the brain tissue lysates from APP knock-out mice.”
Quote in the paperNot a substantial claim
Interpretationown data
The role of miR-33 in regulating ABCA1 and Aβ levels is conserved in mouse and human neural cells.
“Our data also imply that the role of miR-33 in regulating ABCA1 and A␤ levels is conserved in mouse and human neural cells.”
Quote in the paperSubstantial claim
Interpretationown data
miR-33 plays a dominant role in regulating cerebral ABCA1 expression even under normal physiological conditions.
“suggesting that miR-33 plays a dominant role in regulating cerebral ABCA1 expression even under normal physiological conditions.”
Quote in the paperSubstantial claim
Premisecitation
miRNAs often show cell-type, tissue, and species-specific regulation of their target genes.
“Importantly, miRNAs quite often show cell-type, tissue, and species-specific regulation of their target genes due to the differences in their expression levels and the complexity of interaction with their targets in different cellular contexts (Landgraf et al., 2007;Jovic ˇic ´et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Landgraf et al., 2007 source
- cites Jovic ˇic ´et al., 2013
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
miR-33 is a potent regulator of ABCA1 in the brain under normal physiological condition.
“Therefore, our study suggests that miR-33 is a potent regulator of ABCA1 in the brain under normal physiological condition.”
Quote in the paperSubstantial claim
Interpretationown data
miR-33 directly suppresses ABCA1 expression by targeting its 3'UTR region.
“These results demonstrated that miR-33 directly suppresses ABCA1 expression by targeting its 3ЈUTR region.”
Quote in the paperSubstantial claim
Interpretationown data
Brain-specific miR-33 antagonism may be an effective strategy to modulate Aβ levels.
“In addition, our study provides the first evidence that miR-33 is an endogenous regulator of ABCA1 in the brain and brain-specific miR-33 antagonism may be an effective strategy to modulate A␤ levels.”
Quote in the paperSubstantial claim
Interpretationown data
Inhibition of miR-33 increases ApoE lipidation in the brain.
“ApoE-containing lipoprotein particles from the mir-33-deficient mice tended to be larger in size than the particles from WT mice, indicating that inhibition of miR-33 increases ApoE lipidation in the brain (Fig. 3B).”
Quote in the paperSubstantial claim
Premisecitation
ABCA1 levels regulate Aβ deposition in vivo.
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A␤ deposition in vivo (Hirsch-Reinshagen et al., 2004;Wahrle et al., 2004Wahrle et al., , 2005Wahrle et al., , 2008;;Koldamova et al., 2005).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites Hirsch-Reinshagen et al., 2004 source
- cites Wahrle et al., 2004, 2005, 2008
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Koldamova et al., 2005 source
Interpretationown data
Inhibition of cerebral miR-33 effectively reduces Aβ levels in vivo.
“Collectively, these results demonstrated that inhibition of cerebral miR-33 effectively reduces A␤ levels in vivo.”
Quote in the paperSubstantial claim
Premisecitation
Extracellular Aβ degradation by proteases, such as insulin-degrading enzyme, is influenced by the lipidation status of ApoE.
“A previous report demonstrated that extracellular A␤ degradation by proteases, such as insulin-degrading enzyme, is influenced by the lipidation status of ApoE (Jiang et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Jiang et al., 2008 source
Interpretationown data
miR-33 is an endogenous regulator of ABCA1 in the brain.
“In addition, our study provides the first evidence that miR-33 is an endogenous regulator of ABCA1 in the brain and brain-specific miR-33 antagonism may be an effective strategy to modulate A␤ levels.”
Quote in the paperSubstantial claim
Interpretationown data
Impairment of Aβ clearance by miR-33 is mediated by ABCA1.
“These data suggest that impairment of A␤ clearance by miR-33 was mediated by ABCA1.”
Quote in the paperSubstantial claim
Interpretationown data
miR-33 may represent a potential therapeutic target for AD by regulating metabolism of ApoE and Aβ.
“These data suggest that miR-33 may represent a potential therapeutic target for AD by regulating metabolism of ApoE and A␤.”
Quote in the paperSubstantial claim

Classified as probably not a substantial claim. 20
May combine two claims. 16
The quote only partly states this claim. 2

Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Polymorphisms in ABCA1 are possibly associated with AD risk.
“Several genetic association studies have suggested possible association between polymorphisms in ABCA1 and AD risk (Koldamova et al., 2010).”
Quote in the paperNot a substantial claim1 of 1 sources checked
- cites Koldamova et al., 2010 source
May combine two claims.
Premisecitation
ABCA1 is a major cholesterol transporter that transfers cellular cholesterol onto lipid-poor apolipoproteins and regulates ApoE lipidation in the brain.
“ATP-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter that transfers cellular cholesterol onto lipid-poor apolipoproteins and regulates ApoE lipidation in the brain (Koldamova et al., 2014).”
Quote in the paperSubstantial claim1 of 1 sources checked
- cites Koldamova et al., 2014 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
ABCA1 inhibits Aβ secretion in neuronal cells by modulating APP proteolysis and membrane lipid homeostasis.
“several in vitro studies have suggested that ABCA1 inhibits A␤ secretion in neuronal cells by modulating APP proteolysis and membrane lipid homeostasis (Di Paolo and Kim, 2011).”
Quote in the paperNot a substantial claim1 of 1 sources checked
- cites Di Paolo and Kim, 2011 source
  In ‘Role of cholesterol metabolism and transport in amyloidogenesis’ (page not provided), the review reports that increased ABCA1 lowers Aβ levels in cultured cells and that ABCA1 promotes cholesterol efflux. Its discussion of lipid-dependent APP processing is broader; it does not establish that ABCA1 lowers Aβ secretion specifically in neuronal cells by modulating APP proteolysis. (LLM, conf=0.84)
  Experimental — accuracy not yet measured
May combine two claims.
Premisecitation
Pharmacological inhibition of miR-33 increased plasma HDL cholesterol levels in mice and primates, leading to a marked reduction of atherosclerosis phenotypes.
“Pharmacological inhibition of miR-33 increased plasma high-density lipoprotein cholesterol levels in mice (Horie et al., 2010;Najafi-Shoushtari et al., 2010;Rayner et al., 2011a) and primates (Rayner et al., 2011b;Rottiers et al., 2013), leading to a marked reduction of atherosclerosis phenotypes.”
Quote in the paperNot a substantial claim1 of 3 sources checked
- cites Horie et al., 2010 source
- cites Najafi-Shoushtari et al., 2010 source
  The Results report that antisense inhibition of miR-33 significantly increased plasma HDL cholesterol in mice. This paper does not report miR-33 inhibition in primates or demonstrate a reduction in atherosclerosis phenotypes; the citing sentence assigns the primate finding to other citations. (LLM, conf=0.88)
  Experimental — accuracy not yet measured
- cites Rayner et al., 2011a
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
The vast majority of miRNA knock-out mice examined thus far lack any strong phenotypes under normal physiological conditions.
“Somewhat unexpectedly, the vast majority of miRNA knock-out mice examined thus far lack any strong phenotypes under normal physiological conditions (Ebert and Sharp, 2012;Mendell and Olson, 2012).”
Quote in the paperNot a substantial claim2 of 2 sources checked
- cites Ebert and Sharp, 2012 source
  The “Absent and variable phenotypes” section says several mouse miRNA knockouts show no gross phenotype and gives miR-208 as an example with little phenotype under normal conditions. It does not establish that the vast majority of mouse knockouts examined lack strong phenotypes; its “most” statement concerns worms, not mice. No page number is available in our copy. (LLM, conf=0.86)
  Experimental — accuracy not yet measured
- cites Mendell and Olson, 2012 source
  In “Lessons from miRNA loss-of-function studies in model organisms” (page unavailable), the review says the majority of approximately 25 mouse miRNA knockouts examined lacked embryonic developmental defects, and many showed abnormalities only under stress. This supports the general point, but it does not establish that the vast majority lacked any strong phenotype under normal physiological conditions; its explicit mouse finding is narrower and says “majority.” (LLM, conf=0.82)
  Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
There have been several successful cases that have identified small-molecule modulators of miRNAs.
“there have been several successful cases that have identified small-molecule modulators of miRNAs (Velagapudi et al., 2015)”
Quote in the paperNot a substantial claim1 of 1 sources checked
- cites Velagapudi et al., 2015 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
There have been substantial advances in the small RNA delivery technology into the brain.
“there have been substantial advances in the small RNA delivery technology into the brain.”
Quote in the paperNot a substantial claim1 of 3 sources checked
- cites Kumar et al., 2007 source
- cites Pulford et al., 2010 source
- cites Alvarez-Erviti et al., 2011 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Several miRNAs and antisense oligonucleotides (ASOs) are currently under investigation in clinical trials for various diseases.
“Several miRNAs and antisense oligonucleotides (ASOs) are currently under investigation in clinical trials for various diseases (Kanasty et al., 2013;van Rooij and Kauppinen, 2014;Gaudet et al., 2015).”
Quote in the paperNot a substantial claim2 of 3 sources checked
- cites Kanasty et al., 2013 source
- cites van Rooij and Kauppinen, 2014 source
- cites Gaudet et al., 2015 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Pharmacological modulations of disease-associated miRNAs appeared to be well tolerated with promising outcomes in animal models and human patients.
“Pharmacological modulations of disease-associated miRNAs appeared to be well tolerated with promising outcomes in animal models and human patients (van Rooij and Kauppinen, 2014).”
Quote in the paperNot a substantial claim1 of 1 sources checked
- cites van Rooij and Kauppinen, 2014 source
May combine two claims.
Findingown data
Genetic deletion and pharmacological inhibition of miR-33 decrease Aβ levels in the brain.
“For the first time, we demonstrate here that genetic deletion and pharmacological inhibition, using antisense oligonucleotide, of miR-33 decreased A␤ levels in the brain.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
miR-33 is expressed in all neural cell types, with relatively higher expression in neurons compared with glial cells.
“miR-33 was expressed in all neural cell types with relatively higher expression in neurons, compared with glial cells (Fig. 1C).”
Quote in the paperSubstantial claim
The quote only partly states this claim.
Findingown data
Similar results (miR-33 decreases ABCA1 and increases CTFβ and secreted Aβ) are observed in human H4 neuroglioma cells expressing APPsw.
“Similar results were observed in human H4 neuroglioma cells expressing APPsw transfected with miR-33 (Fig. 4C,D).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Deletion of miR-33 increased ApoE lipidation and facilitated extracellular Aβ degradation, leading to significant reduction of brain Aβ levels, compared with WT.
“deletion of miR-33 increased ApoE lipidation and facilitated extracellular A␤ degradation, leading to significant reduction of brain A␤ levels, compared with WT.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Overexpression of miR-33 impaired ApoE lipidation and decreased Aβ clearance by neuronal and glial cells.
“overexpression of miR-33 impaired ApoE lipidation and decreased A␤ clearance by neuronal and glial cells.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
ABCA1 levels were dramatically increased in cortex of mir-33 knock-out mice at 4 months of age, without altering APP levels.
“Compared with WT mice (n ϭ 8), ABCA1 levels were dramatically increased in cortex of mir-33 knock-out mice (n ϭ 7) at 4 months of age, without altering APP levels (A, B).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
In the anti-miR-33 treatment group, Aβ40 levels were significantly decreased and Aβ42 levels showed a trend toward decrease, compared with the mismatch control.
“In the anti-miR-33 treatment group (n ϭ 9), A␤ 40 levels were significantly decreased ( p ϭ 0.0286) (C) and A␤ 42 levels showed a trend toward decrease ( p ϭ 0.0954) (D), compared with the mismatch control (n ϭ 6).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
ApoE is a major cholesterol carrier in the brain.
“ApoE is a major cholesterol carrier in the brain (Kim et al., 2009a).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kim et al., 2009a
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
APOE genotype is the strongest genetic risk factor for AD, with the ε4 allele acting as an AD risk factor, whereas the ε2 allele is protective.
“Apolipoprotein E (APOE) genotype is the strongest genetic risk factor for AD, with the ␧4 allele acting as an AD risk factor, whereas the ␧2 allele is protective (Kim et al., 2009a).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kim et al., 2009a
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
The main effect of APOE isoforms on AD risk is via their effect on Aβ metabolism.
“Previous studies have suggested that the main effect of APOE isoforms on AD risk is via their effect on A␤ metabolism (Kim et al., 2009a).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kim et al., 2009a
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Premisecitation
Dysregulation of Aβ peptide metabolism is hypothesized to initiate pathogenic cascades that lead to Alzheimer's disease (AD).
“Dysregulation of A␤ peptide metabolism is hypothesized to initiate pathogenic cascades that lead to Alzheimer's disease (AD) (Haass and Selkoe, 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Haass and Selkoe, 2007 source
May combine two claims.
Interpretationown data
miR-33 regulates extracellular Aβ levels by modulating Aβ secretion as well as Aβ degradation.
“Together, our data suggest that miR-33 regulates extracellular A␤ levels by modulating A␤ secretion as well as A␤ degradation.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
Cholesterol efflux experiments were repeated 3 times.
“Experiments were repeated 3 times.”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim.
Premisecitation
miRNAs often show strong cell type- and tissue-specific regulation of their targets.
“miRNAs often show strong cell typeand tissue-specific regulation of their targets (Landgraf et al., 2007;Jovic ˇic ´et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Landgraf et al., 2007 source
- cites Jovic ˇic ´et al., 2013
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Study design and conductown data
The data did not violate the assumptions of parametric testing before analysis with a two-tailed Student's t test.
“After confirmation that the data did not violate the assumptions of parametric testing, the data were analyzed with a two-tailed Student's t test (Graph-Pad Prism 5).”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
miR-33 regulates Aβ secretion via modulating ABCA1, rather than other genes.
“In the presence of miR-33 resistant Abca1 without 3ЈUTR (Abca1 ORF), miR-33 did not affect ABCA1 levels nor A␤ levels in N2a cells expressing APPsw, suggesting that miR-33 regulates A␤ secretion via modulating ABCA1, rather than other genes (Fig. 4E,F).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.
Study design and conductown data
All experiments in the Aβ secretion assay were performed in duplicate or triplicate and repeated independently 3 times.
“All experiments were performed in duplicate or triplicate and repeated independently 3 times.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
Each transfection condition in the luciferase assay was performed in triplicate, and the experiments were repeated twice.
“Each transfection condition was performed in triplicate, and the experiments were repeated twice.”
Quote in the paperNot a substantial claim
May combine two claims.
Interpretationown data
miR-33 regulates ApoE lipidation as well as extracellular ApoE levels in the brain.
“Collectively, these data suggest that miR-33 regulates ApoE lipidation as well as extracellular ApoE levels in the brain.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Interpretationcitation
ABCA1 regulation by miR-33 in the periphery does not necessarily mean that miR-33 will regulate ABCA1 in the brain.
“Therefore, ABCA1 regulation by miR-33 in the periphery does not necessarily mean that miR-33 will regulate ABCA1 in the brain.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
ABCA1 expression is regulated by miR-33 in the periphery.
“Previously, we demonstrated that ABCA1 expression is regulated by miR-33 in the periphery (Horie et al., 2010;Rayner et al., 2010Rayner et al., , 2011a,b),b).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Horie et al., 2010 source
- cites Rayner et al., 2010, 2011a,b
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductown data
miR-33 is selectively deleted in cortex of miR-33(-/-) mice without altering the expression of its host gene, SREBF2, in cortex.
“miR-33 is selectively deleted in cortex of miR-33 (Ϫ/Ϫ) mice without altering the expression of its host gene, SREBF2, in cortex.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Intrathecal ASO injection to human was successfully completed in the Phase I and II clinical trials.
“Recently, intrathecal ASO injection to human was successfully completed in the Phase I and II clinical trials (Faravelli et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Faravelli et al., 2015 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Both trials demonstrated that intrathecal ASO injection is safe and effective.
“Both trials demonstrated that intrathecal ASO injection is safe and effective.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Faravelli et al., 2015 source

33 of 33

The paper relies on this without support.
The physiological function of miR-33 in the CNS and whether miR-33 has any pathological role in AD have never been investigated.
“However, the physiological function of miR-33 in the CNS and whether miR-33 has any pathological role in AD have never been investigated.”
The paper relies on this without support.
The regulation of brain lipid metabolism, in particular by microRNAs, is relatively unknown.
“Although there have been studies on brain lipid metabolism, its regulation, in particular by microRNAs, is relatively unknown.”
The paper relies on this without support.
Whether pharmacological inhibition of a miRNA can be a practical strategy to regulate brain Aβ levels in vivo has not yet been demonstrated.
“Although several in vitro studies have implicated miRNAs in AD pathogenesis, whether pharmacological inhibition of a miRNA can be a practical strategy to regulate brain A␤ levels in vivo has not yet been demonstrated.”
The paper relies on this without support.
Brain lipid metabolism is largely separated from the periphery due to the blood-brain barrier and different repertoire of lipoproteins.
“Brain lipid metabolism is largely separated from the periphery due to blood-brain barrier and different repertoire of lipoproteins.”
The paper relies on this without support.
Our understanding of how endogenous Aβ levels are regulated is still limited.
“Despite the critical role of A␤ metabolism in AD pathogenesis, our understanding of how endogenous A␤ levels are regulated is still limited.”
The paper relies on this without support.
miRNA overexpression over a certain physiological level may lead to an artificial effect by surpassing biological buffering capacity of the cells.
“miRNA overexpression over a certain physiological level may lead to an artificial effect by surpassing biological buffering capacity of the cells.”

6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

miR-33 increases extracellular Aβ levels in mouse and human neuronal cells.
“miR-33 increased extracellular Aβ levels in mouse and human neuronal cells.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [127]
The section on Aβ secretion and clearance reports increased secreted Aβ after miR-33 transfection in mouse N2a cells, with similar results in human H4 cells. The human cells are identified as neuroglioma cells, not neuronal cells, so the claim overstates that cell-type detail. (LLM, conf=0.85)
Experimental — accuracy not yet measured
ABCA1 is redundantly targeted by miR-106b, miR-758, and miR-33 in the brain.
“ABCA1 is redundantly targeted by miR-106b, miR-758, and miR-33 in the brain.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [127]
The section “miR-33 suppresses ABCA1 expression in the brain” (page not provided) shows that miR-33 directly targets ABCA1 in neural cells, and the Discussion confirms its effect in the brain. The copy does not establish that miR-106b and miR-758 also target ABCA1 in the brain, or that the three act redundantly; it instead describes miR-33 as a dominant regulator of cerebral ABCA1. (LLM, conf=0.88)
Experimental — accuracy not yet measured
miR-33 negatively regulates ABCA1 in both the periphery and the brain.
“Previously, it was shown that miR‐33 negatively regulates ABCA1 in both the periphery and the brain. 15 , 16 , 17 , 18”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [17]
Deletion of the mir-33 gene increases the lipidation of apoE in the brains of wild-type mice.
“Furthermore, we demonstrated that deletion of the mir‐33 gene increases the lipidation of apoE in the brains of wild‐type mice. 17”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [17]
miR-33 negatively regulates ABCA1 protein levels.
“Previously, miR‐33 was shown to negatively regulate ABCA1 protein levels. 17 , 18”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [17]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Conflicting collection times for astrocyte-conditioned media
Minor
The methods say fresh media were added 48 hours after transfection and conditioned media were collected 24 hours later. Figure 6 instead says conditioned media were collected 48 hours after transfection.
Figure 6 reports a statistical test not described in the methods
Minor
The statistical-analysis section says the data were analyzed with a two-tailed Student's t test, but Figure 6 reports a two-way ANOVA.

2 of 2

Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. A. (2011) · Nature Biotechnology · doi:10.1038/nbt.1807 · Cited by 4,930 · cited 1× · see citing works
“For example, conjugation with neurotrophic virus peptide and exosome- or liposome-based nanoparticles are promising avenues of future research (Kumar et al., 2007; Pulford et al., 2010; Alvarez-Erviti et al., 2011; Roshan et al., 2014).”
Background
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · cited 1× · see citing works
“Dysregulation of A peptide metabolism is hypothesized to initiate pathogenic cascades that lead to Alzheimer’s disease (AD) (Haass and Selkoe, 2007).”
Background
A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing
Landgraf, P., Rusu, M., Sheridan, R., Sewer, A., Iovino, N., Aravin, A., Pfeffer, S., Rice, A., Kamphorst, A. O., Landthaler, M., et al. (2007) · Cell · doi:10.1016/j.cell.2007.04.040 · Cited by 3,626 · see citing works
Delivery materials for siRNA therapeutics
Kanasty, R., Dorkin, J. R., Vegas, A., & Anderson, D. (2013) · Nature Materials · doi:10.1038/nmat3765 · Cited by 1,800 · cited 1× · see citing works
“Several miRNAs and antisense oligonucleotides (ASOs) are currently under investigation in clinical trials for various diseases (Kanasty et al., 2013; van Rooij and Kauppinen, 2014; Gaudet et al., 2015).”
Background
MicroRNAs in Stress Signaling and Human Disease
Mendell, J. T., & Olson, E. N. (2012) · Cell · doi:10.1016/j.cell.2012.02.005 · Cited by 1,673 · cited 2× · see citing works
“In many cases, miRNA knock-out mice showed no gross phenotype under normal physiological conditions, possibly due to the functional redundancy of multiple miRNAs for the same target gene (Ebert and Sharp, 2012; Mendell and Olson, 2012).”
Background
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Self-citation
Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · cited 2× · see citing works
“Twomonth-old APPsw/PSEN1 9 (APP/PS1) transgenic mice overexpressing Swedish mutant APP695 and human PSEN1 with an exon 9 deletion (Jankowsky et al., 2004) were treated with 30 g/d of anti-miR-33 or mismatch control for 4 weeks via intracerebroventricular infusion using an osmotic pump (Alzet)…”
Method
Roles for MicroRNAs in Conferring Robustness to Biological Processes
Ebert, M. S., & Sharp, P. A. (2012) · Cell · doi:10.1016/j.cell.2012.04.005 · Cited by 1,564 · cited 2× · see citing works
“In many cases, miRNA knock-out mice showed no gross phenotype under normal physiological conditions, possibly due to the functional redundancy of multiple miRNAs for the same target gene (Ebert and Sharp, 2012; Mendell and Olson, 2012).”
Background
MiR-33 Contributes to the Regulation of Cholesterol Homeostasis
Rayner, K. J., Suárez, Y., Dávalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., & Fernández-Hernando, C. (2010) · Science · doi:10.1126/science.1189862 · Cited by 1,260 · cited 1× · see citing works
“Previously, we demonstrated that ABCA1 expression is regulated by miR-33 in the periphery (Horie et al., 2010; Rayner et al., 2010, 2011a,b).”
Background
Transvascular delivery of small interfering RNA to the central nervous system
Kumar, P., Wu, H., McBride, J. L., Jung, K.-E., Hee Kim, M., Davidson, B. L., Kyung Lee, S., Shankar, P., & Manjunath, N. (2007) · Nature · doi:10.1038/nature05901 · Cited by 1,246 · cited 1× · see citing works
“For example, conjugation with neurotrophic virus peptide and exosome- or liposome-based nanoparticles are promising avenues of future research (Kumar et al., 2007; Pulford et al., 2010; Alvarez-Erviti et al., 2011; Roshan et al., 2014).”
Background
Linking lipids to Alzheimer's disease: cholesterol and beyond
Di Paolo, G., & Kim, T.-W. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3012 · Cited by 972 · see citing works
MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis
Najafi-Shoushtari, S. H., Kristo, F., Li, Y., Shioda, T., Cohen, D. E., Gerszten, R. E., & Näär, A. M. (2010) · Science · doi:10.1126/science.1189123 · Cited by 957 · cited 2× · see citing works
“Pharmacological inhibition of miR-33 increased plasma high-density lipoprotein cholesterol levels in mice (Horie et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2011a) and primates (Rayner et al.”
Background
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · cited 3× · see citing works
“In addition to its role in A secretion, ABCA1 has been also shown to decrease A levels by promoting extracellular A clearance in both neurons and glial cells (Jiang et al., 2008; Kim et al., 2012).”
BackgroundSelf-citation
Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Rayner, K. J., Esau, C. C., Hussain, F. N., McDaniel, A. L., Marshall, S. M., van Gils, J. M., Ray, T. D., Sheedy, F. J., Goedeke, L., Liu, X., et al. (2011) · Nature · doi:10.1038/nature10486 · Cited by 706 · cited 3× · see citing works
“Previously, we demonstrated that ABCA1 expression is regulated by miR-33 in the periphery (Horie et al., 2010; Rayner et al., 2010, 2011a,b).”
BackgroundMethodSelf-citation
Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis
Rayner, K. J., Sheedy, F. J., Esau, C. C., Hussain, F. N., Temel, R. E., Parathath, S., van Gils, J. M., Rayner, A. J., Chang, A. N., Suarez, Y., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57275 · Cited by 690 · cited 3× · see citing works
“Previously, we demonstrated that ABCA1 expression is regulated by miR-33 in the periphery (Horie et al., 2010; Rayner et al., 2010, 2011a,b).”
BackgroundMethodSelf-citation
Development of microRNA therapeutics is coming of age
van Rooij, E., & Kauppinen, S. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201100899 · Cited by 625 · cited 2× · see citing works
“Several miRNAs and antisense oligonucleotides (ASOs) are currently under investigation in clinical trials for various diseases (Kanasty et al., 2013; van Rooij and Kauppinen, 2014; Gaudet et al., 2015).”
Background
Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia
Gaudet, D., Alexander, V. J., Baker, B. F., Brisson, D., Tremblay, K., Singleton, W., Geary, R. S., Hughes, S. G., Viney, N. J., Graham, M. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1400283 · Cited by 528 · see citing works
ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE
Wahrle, S. E., Jiang, H., Parsadanian, M., Legleiter, J., Han, X., Fryer, J. D., Kowalewski, T., & Holtzman, D. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407963200 · Cited by 474 · cited 1× · see citing works
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A deposition in vivo (HirschReinshagen et al., 2004; Wahrle et al., 2004, 2005, 2008; Koldamova et al., 2005).”
BackgroundSelf-citation
MicroRNA regulation of Alzheimer's Amyloid precursor protein expression
Hébert, S. S., Horré, K., Nicolaï, L., Bergmans, B., Papadopoulou, A. S., Delacourte, A., & De Strooper, B. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.11.009 · Cited by 436 · cited 2× · see citing works
“Recently, microRNAs (miRNAs) have emerged as a new class of therapeutic targets for various diseases, including neurodegenerative disorders (Nelson and Keller, 2007; Hébert et al., 2009).”
Background
Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain
Hirsch-Reinshagen, V., Zhou, S., Burgess, B. L., Bernier, L., McIsaac, S. A., Chan, J. Y., Tansley, G. H., Cohn, J. S., Hayden, M. R., & Wellington, C. L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407962200 · Cited by 385 · see citing works
MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 ( <i>Srebp2</i> ) regulates HDL in vivo
Horie, T., Ono, K., Horiguchi, M., Nishi, H., Nakamura, T., Nagao, K., Kinoshita, M., Kuwabara, Y., Marusawa, H., Iwanaga, Y., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008499107 · Cited by 384 · cited 6× · see citing works
“We previously reported the generation of the mir-33 knock-out mice (Horie et al., 2010).”
BackgroundInfluentialSelf-citation
Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33622 · Cited by 370 · cited 2× · see citing works
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A deposition in vivo (HirschReinshagen et al., 2004; Wahrle et al., 2004, 2005, 2008; Koldamova et al., 2005).”
BackgroundResultSelf-citation
Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice
Koldamova, R., Staufenbiel, M., & Lefterov, I. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504513200 · Cited by 350 · cited 1× · see citing works
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A deposition in vivo (HirschReinshagen et al., 2004; Wahrle et al., 2004, 2005, 2008; Koldamova et al., 2005).”
Background
Deletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Hartman, R. E., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508780200 · Cited by 325 · cited 1× · see citing works
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A deposition in vivo (HirschReinshagen et al., 2004; Wahrle et al., 2004, 2005, 2008; Koldamova et al., 2005).”
BackgroundSelf-citation
Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl–Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates
Rigo, F., Chun, S. J., Norris, D. A., Hung, G., Lee, S., Matson, J., Fey, R. A., Gaus, H., Hua, Y., Grundy, J. S., et al. (2014) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.212407 · Cited by 283 · see citing works
Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance
Kim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · cited 8× · see citing works
“Mounting evidence has demonstrated that dysregulation of cholesterol metabolism is implicated in AD pathogenesis (Kim et al., 2009a; Di Paolo and Kim, 2011).”
BackgroundMethodInfluentialSelf-citation
Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes
Jovičić, A., Roshan, R., Moisoi, N., Pradervand, S., Moser, R., Pillai, B., & Luthi-Carter, R. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.0600-12.2013 · Cited by 251 · cited 8× · see citing works
“Many miRNAs show unique cell-type-specific expression patterns in different neural cell types, such as neurons, astrocytes, and microglia (Jovičić et al., 2013).”
BackgroundInfluential
22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid β Secretion
Koldamova, R. P., Lefterov, I. M., Ikonomovic, M. D., Skoko, J., Lefterov, P. I., Isanski, B. A., DeKosky, S. T., & Lazo, J. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300044200 · Cited by 237 · cited 1× · see citing works
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A production, although how ABCA1 regulates A production remains to be clarified (Koldamova et al., 2003; Sun et al., 2003; Kim et al., 2007).”
Background
Role of ABCG1 and ABCA1 in Regulation of Neuronal Cholesterol Efflux to Apolipoprotein E Discs and Suppression of Amyloid-β Peptide Generation
Kim, W. S., Rahmanto, A. S., Kamili, A., Rye, K.-A., Guillemin, G. J., Gelissen, I. C., Jessup, W., Hill, A. F., & Garner, B. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607831200 · Cited by 191 · cited 1× · see citing works
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A production, although how ABCA1 regulates A production remains to be clarified (Koldamova et al., 2003; Sun et al., 2003; Kim et al., 2007).”
Background
Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion
Sun, Y., Yao, J., Kim, T.-W., & Tall, A. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300760200 · Cited by 179 · cited 5× · see citing works
“…ApoE levels in the brain. miR-33 regulates A secretion and A clearance in neural cells We and others previously demonstrated that ABCA1 decreases A secretion by inhibiting BACE1-mediated APP cleavage without affecting BACE1 expression in neuronal cells (Sun et al., 2003; Kim et al., 2012).”
BackgroundResultInfluential
miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression
Kim, J., Yoon, H., Ramírez, C. M., Lee, S.-M., Hoe, H.-S., Fernández-Hernando, C., & Kim, J. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2011.11.010 · Cited by 173 · cited 12× · see citing works
“Western blots were performed as previously described (Kim et al., 2009b, 2012).”
BackgroundMethodResultInfluentialSelf-citation
Reducing Human Apolipoprotein E Levels Attenuates Age-Dependent Aβ Accumulation in Mutant Human Amyloid Precursor Protein Transgenic Mice
Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0033-12.2012 · Cited by 170 · cited 2× · see citing works
“We provide a unique approach for AD therapeutics to increase ApoE lipidation and reduce A levels via pharmacological inhibition of microRNA in vivo. and lipidation status have been shown to strongly influence A metabolism (Kim et al., 2009a,b; Bien-Ly et al., 2012).”
Background
Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice
Roshan, R., Shridhar, S., Sarangdhar, M. A., Banik, A., Chawla, M., Garg, M., Singh, V. P., & Pillai, B. (2014) · RNA · doi:10.1261/rna.044008.113 · Cited by 146 · see citing works
ATP-binding cassette transporter A1: From metabolism to neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.007 · Cited by 144 · cited 1× · see citing works
“ATP-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter that transfers cellular cholesterol onto lipid-poor apolipoproteins and regulates ApoE lipidation in the brain (Koldamova et al., 2014).”
Background
Spinal muscular atrophy—recent therapeutic advances for an old challenge
Faravelli, I., Nizzardo, M., Comi, G. P., & Corti, S. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.77 · Cited by 138 · cited 1× · see citing works
“Recently, intrathecal ASO injection to human was successfully completed in the Phase I and II clinical trials (Faravelli et al., 2015).”
Background
Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR
Rottiers, V., Obad, S., Petri, A., McGarrah, R., Lindholm, M. W., Black, J. C., Sinha, S., Goody, R. J., Lawrence, M. S., deLemos, A. S., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006840 · Cited by 121 · cited 3× · see citing works
“…ApoE levels in the brain. miR-33 regulates A secretion and A clearance in neural cells We and others previously demonstrated that ABCA1 decreases A secretion by inhibiting BACE1-mediated APP cleavage without affecting BACE1 expression in neuronal cells (Sun et al., 2003; Kim et al., 2012).”
BackgroundResultInfluential
BRI2 (ITM2b) Inhibits A Deposition In Vivo
Kim, J., Miller, V. M., Levites, Y., West, K. J., Zwizinski, C. W., Moore, B. D., Troendle, F. J., Bann, M., Verbeeck, C., Price, R. W., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0891-08.2008 · Cited by 113 · cited 1× · see citing works
“Cortical tissues were lysed in 0.2% diethylamine/50 mM NaCl lysis buffer with EDTA-free protease inhibitor mixture (Roche) by sonication, as previously described (Kim et al., 2008).”
MethodInfluentialSelf-citation
RNA in Brain Disease
Nelson, P. T., & Keller, J. N. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000240474.27791.f3 · Cited by 108 · cited 2× · see citing works
“Recently, microRNAs (miRNAs) have emerged as a new class of therapeutic targets for various diseases, including neurodegenerative disorders (Nelson and Keller, 2007; Hébert et al., 2009).”
Background
The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.02.010 · Cited by 102 · cited 1× · see citing works
“Several genetic association studies have suggested possible association between polymorphisms in ABCA1 and AD risk (Koldamova et al., 2010).”
Background
Liposome-siRNA-Peptide Complexes Cross the Blood-Brain Barrier and Significantly Decrease PrPC on Neuronal Cells and PrPRES in Infected Cell Cultures
Pulford, B., Reim, N., Bell, A., Veatch, J., Forster, G., Bender, H., Meyerett, C., Hafeman, S., Michel, B., Johnson, T., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011085 · Cited by 85 · cited 1× · see citing works
“For example, conjugation with neurotrophic virus peptide and exosome- or liposome-based nanoparticles are promising avenues of future research (Kumar et al., 2007; Pulford et al., 2010; Alvarez-Erviti et al., 2011; Roshan et al., 2014).”
Background
Small molecule chemical probes of microRNA function
Velagapudi, S. P., Vummidi, B. R., & Disney, M. D. (2015) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2014.10.024 · Cited by 46 · cited 1× · see citing works
“In addition to ASOs, there have been several successful cases that have identified small-molecule modulators of miRNAs (Velagapudi et al., 2015), further expanding the roles of miRNAs from diagnostic tools to therapeutic targets of diseases.”
Background

Flagged first, then by citations

Sorted by citations

Metazoan MicroRNAs
Bartel, D. P. (2018) · Cell · doi:10.1016/j.cell.2018.03.006 · Cited by 3,751 · see citing works
“, 2010); increased ApoE lipidation and Ab degradation in the brain (Kim et al., 2015); increased obesity and liver steatosis on high-fat diet (Horie et al.”
Background
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
“Targeting of miRNA-33 via ASO results in increased ABCA1 levels, elevated apoE lipidation, and decreased Aβ levels in mouse models [233].”
Background
APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306 · see citing works
“Intracerebroventricular infusion of anti-miR-33 oligonucleotides reduces cortical Aβ40 levels in 3-month-old APP/PS1 mice [334].”
Background
Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases
Wu, Y.-Y., & Kuo, H.-C. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-00636-z · Cited by 213 · see citing works
“The deletion of miR-33 has been linked to AD pathology in APPswe/PESN1ΔE9 mice [118].”
Background
Noncoding RNAs in Alzheimer's disease
Idda, M. L., Munk, R. B., Abdelmohsen, K., & Gorospe, M. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1463 · Cited by 206 · see citing works
“Deletion of miR-33 in mice increased the levels of ATP-binding cassette transporter (ABCA1) and APOE lipidation, while it decreased Aβ levels in the cortex (Kim et al., 2015).”
Background
Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease
Liao, F., Yoon, H., & Kim, J. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000383 · Cited by 191 · see citing works
Self-citation
ApoE Lipidation as a therapeutic target in Alzheimer’s disease
Lanfranco, M. F., Ng, C. A., & Rebeck, G. W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176336 · Cited by 189 · see citing works
Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function
Battista, A. M. D., Heinsinger, N. M., & Rebeck, G. W. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160401115127 · Cited by 184 · see citing works
Oligonucleotide therapies for disorders of the nervous system
Khorkova, O., & Wahlestedt, C. (2017) · Nature Biotechnology · doi:10.1038/nbt.3784 · Cited by 179 · see citing works
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
“Inhibition of microRNA-33 by ASOs in cultured neurons and APP transgenic mice reduces Aβ levels [127, 128].”
Background
miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1)
Kim, J., Fiesel, F. C., Belmonte, K. C., Hudec, R., Wang, W.-X., Kim, C., Nelson, P. T., Springer, W., & Kim, J. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0121-4 · Cited by 163 · see citing works
Self-citation
The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease
Jacobo‐Albavera, L., Domínguez‐Pérez, M., Medina-Leyte, D. J., González-Garrido, A., & Villarreal-Molina, M. T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041593 · Cited by 163 · see citing works
“Conversely, selective ABCA1 overexpression in AD mouse models led to increased CNS apoE lipidation and sharply decreased amyloid deposition [168], while ABCA1 upregulation by miRNA-33 inhibition was found to increase apoE lipidation and to decrease Aβ levels in the brain [169].”
Background
Apolipoprotein E and Alzheimer's disease
Troutwine, B., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.002 · Cited by 164 · see citing works
Cellular cholesterol homeostasis and Alzheimer’s disease
Chang, T.-Y., Yamauchi, Y., Hasan, M. T., & Chang, C. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075630 · Cited by 155 · see citing works
Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer’s disease: An integrative review
Millan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer's disease
Reddy, P. H., Tonk, S., Kumar, S., Vijayan, M., Kandimalla, R., Kuruva, C. S., & Reddy, A. P. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.067 · Cited by 119 · see citing works
The promise of microRNA-based therapies in Alzheimer’s disease: challenges and perspectives
Walgrave, H., Zhou, L., Strooper, B. D., & Salta, E. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00496-7 · Cited by 132 · see citing works
Alzheimer’s Disorder: Epigenetic Connection and Associated Risk Factors
Sharma, V., Mehta, V., & Singh, T. G. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200128125641 · Cited by 121 · see citing works
The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE
Jun, S., Datta, S., Wang, L., Pegany, R. B., Cano, M., & Handa, J. T. (2018) · Experimental Eye Research · doi:10.1016/j.exer.2018.09.023 · Cited by 115 · see citing works
Potential Roles of Exosomal MicroRNAs as Diagnostic Biomarkers and Therapeutic Application in Alzheimer’s Disease
Chen, J.-J., Zhao, B., Zhao, J., & Li, S. (2017) · Neural Plasticity · doi:10.1155/2017/7027380 · Cited by 113 · see citing works
Precision pharmacology for Alzheimer’s disease
Hampel, H. J., Vergallo, A., Aguilar, L. F., Benda, N., Broich, K., Cuello, A. C., Cummings, J. L., Dubois, B., Federoff, H. J., Fiandaca, M. S., et al. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.014 · Cited by 112 · see citing works
MicroRNAs in Alzheimer’s Disease: Function and Potential Applications as Diagnostic Biomarkers
Wei, W., Wang, Z.-Y., Ma, L.-N., Zhang, T.-T., Cao, Y., & Li, H. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00160 · Cited by 102 · see citing works
“…al., 2016 miR-322 ↑ The hippocampus of Tg2576 AD transgenic mouse BDNF-TrkB; tau hyperphosphorylation ↑ Zhang et al., 2018 miR-33 ↑ Brain of miR-33 (−/−) mice and primary neural cells ABCA1; Metabolism of ApoE and Aβ; Aβ ↑ Kim et al., 2015 miR-330 ↓ AD mouse and primary neuron cells VAV1; MAPK…”
Background
Specific Disruption of Abca1 Targeting Largely Mimics the Effects of miR-33 Knockout on Macrophage Cholesterol Efflux and Atherosclerotic Plaque Development
Price, N., Rotllan, N., Zhang, X.-B., Canfrán-Duque, A., Nottoli, T., Suárez, Y., & Fernández-Hernando, C. (2019) · Circulation Research · doi:10.1161/circresaha.118.314415 · Cited by 80 · see citing works
Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer's disease
Kumar, S., Reddy, A. P., Yin, X., & Reddy, P. H. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.06.006 · Cited by 97 · see citing works
Cholesterol homeostasis: Researching a dialogue between the brain and peripheral tissues
Gliozzi, M., Musolino, V., Bosco, F., Scicchitano, M., Scarano, F., Nucera, S., Zito, M. C., Ruga, S., Carresi, C., Macrì, R., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105215 · Cited by 92 · see citing works
The neurobiology of non-coding RNAs and Alzheimer’s disease pathogenesis: Pathways, mechanisms and translational opportunities
Lauretti, E., Dabrowski, K. R., & Praticò, D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101425 · Cited by 94 · see citing works
Role of Epigenetics in Alzheimer’s Disease Pathogenesis
Stoccoro, A., & Coppedè, F. (2018) · Neurodegenerative Disease Management · doi:10.2217/nmt-2018-0004 · Cited by 90 · see citing works
MicroRNAs, Aging, Cellular Senescence, and Alzheimer's Disease
Reddy, P. H., Williams, J. M., Smith, F., Bhatti, J. S., Kumar, S., Vijayan, M., Kandimalla, R. J. L., Kuruva, C. S., Wang, R., Mańczak, M., et al. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2016.12.009 · Cited by 87 · see citing works
Environmental and Dietary Exposure to Copper and Its Cellular Mechanisms Linking to Alzheimer’s Disease
Hsu, H.-W., Bondy, S. C., & Kitazawa, M. (2018) · Toxicological Sciences · doi:10.1093/toxsci/kfy025 · Cited by 88 · see citing works
“ABCA1 upregulation generally promotes cellular cholesterol efflux through ApoE lipidation and lowers cellular Ab generation (Kim et al., 2015).”
Background
Over-expression of miR-34a induces rapid cognitive impairment and Alzheimer’s disease-like pathology
Sarkar, S., Engler-Chiurazzi, E. B., Cavendish, J. Z., Povroznik, J. M., Russell, A. E., Quintana, D. D., Mathers, P. H., & Simpkins, J. W. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146327 · Cited by 86 · see citing works
“Recent evidence suggests that several miRNAs are closely correlated with AD pathology by mechanisms such as regulation of the production of Aβ and phosphorylation of tau and inflammatory responses (Hebert et al., 2008; Kim et al., 2015; Smith et al., 2011; Vilardo et al., 2010).”
Background
MicroRNA 7 Impairs Insulin Signaling and Regulates A <i>β</i> Levels through Posttranscriptional Regulation of the Insulin Receptor Substrate 2, Insulin Receptor, Insulin-Degrading Enzyme, and Liver X Receptor Pathway
Fernández-de Frutos, M., Galán-Chilet, I., Goedeke, L., Kim, B., Pardo-Marqués, V., Pérez-García, A., Herrero, J. I., Fernández-Hernando, C., Kim, J., & Ramírez, C. M. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00170-19 · Cited by 82 · see citing works
Self-citation
Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 82 · see citing works
Antisense oligonucleotides for Alzheimer's disease therapy: from the mRNA to miRNA paradigm
Grabowska, W., Want, A., Leszek, J., & Wojda, U. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103691 · Cited by 79 · see citing works
“Administration of a miR-33-5p antagomiR resulted in elevated ABCA1 levels in wild-type C57BL/B6 mice [79] and decreased Ab level in cortices of APP/PS1 mice [80].”
Background
MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: relevance to Alzheimer’s disease
Kumar, S., Morton, H., Sawant, N., Orlov, E., Bunquin, L. E., Pradeepkiran, J. A., Alvir, R., & Reddy, P. H. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102182 · Cited by 75 · see citing works
miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP
Jian, C., Lu, M., Zhang, Z., Liu, L., Li, X., Huang, F., Xu, N., Qin, L., Zhang, Q., & Zou, D. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.05.023 · Cited by 74 · see citing works
MicroRNAs in central nervous system diseases: A prospective role in regulating blood-brain barrier integrity
Ma, F., Zhang, X., & Yin, K. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113094 · Cited by 72 · see citing works
“MiR-33 regulates the Aβ level in mouse brains by regulating the ATP-binding cassette transporter A1 (ABCA1), a key regulator of apolipoprotein E lipidation (Kim et al., 2015).”
Background
Alzheimer’s Disease and ncRNAs
Maoz, R., Garfinkel, B. P., & Soreq, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-53889-1_18 · Cited by 72 · see citing works
MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms
Dehghani, R., Rahmani, F., & Rezaei, N. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0042 · Cited by 72 · see citing works
“miRNA 33 Downregulation ApoE, ABCA1, SREBF1-2 Aβ metabolism (Kim et al., 2015) miRNA 155 Upregulation P53, c-maf Neuroinflammation (Guedes et al.”
Influential
The Eminent Role of microRNAs in the Pathogenesis of Alzheimer's Disease
Samadian, M. M., Gholipour, M., Hajiesmaeili, M., Taheri, M. N., & Ghafouri‐Fard, S. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.641080 · Cited by 70 · see citing works
MicroRNAs in brain aging
Danka Mohammed, C. P., Park, J. S., Nam, H. G., & Kim, K. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.01.007 · Cited by 68 · see citing works
The Role of Non-coding RNAs in Alzheimer’s Disease: From Regulated Mechanism to Therapeutic Targets and Diagnostic Biomarkers
Zhang, Y., Zhao, Y., Ao, X., Yu, W., Zhang, L., Wang, Y., & Chang, W. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.654978 · Cited by 68 · see citing works
microRNAs in Neurodegeneration: Current Findings and Potential Impacts
Sharma, S., & Lu, H. (2018) · Journal of Alzheimer’s Disease & Parkinsonism · doi:10.4172/2161-0460.1000420 · Cited by 66 · see citing works
Prenatal Exposure to Benzophenone-3 Impairs Autophagy, Disrupts RXRs/PPARγ Signaling, and Alters Epigenetic and Post-Translational Statuses in Brain Neurons
Wnuk, A., Rzemieniec, J., Staroń, J., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1401-5 · Cited by 67 · see citing works
Roles of Non-Coding RNA in Alzheimer’s Disease Pathophysiology
Olufunmilayo, E. O., & Holsinger, R. M. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512498 · Cited by 66 · see citing works
New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer’s disease
Cao, Y., Zhao, L., Chen, Z., & Li, S. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1430465 · Cited by 58 · see citing works
miR-137 attenuates Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in Neuro2a cells
He, D., Tan, J., & Zhang, J. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.144 · Cited by 61 · see citing works
Small molecule inducers of ABCA1 and apoE that act through indirect activation of the LXR pathway
Fan, J., Zhao, R. Q., Parro, C., Zhao, W., Chou, H.-Y., Robert, J., Deeb, T. Z., Raynoschek, C., Barichievy, S., Engkvist, O., et al. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m081851 · Cited by 50 · see citing works
microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity
Horie, T., Nakao, T., Miyasaka, Y., Nishino, T., Matsumura, S., Nakazeki, F., Ide, Y., Kimura, M., Tsuji, S., Rodriguez, R. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21107-5 · Cited by 49 · see citing works
Self-citation
Inhibition of microRNA-155 Alleviates Cognitive Impairment in Alzheimer’s Disease and Involvement of Neuroinflammation
Liu, D., Zhao, D., Zhao, Y., Wang, Y., Zhao, Y., & Wen, C. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190503145207 · Cited by 49 · see citing works
Free radical biology in neurological manifestations: mechanisms to therapeutics interventions
Tripathi, R. S., Gupta, R. V., Sahu, M., Srivastava, D., Das, A., Ambasta, R. K., & Kumar, P. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-021-16693-2 · Cited by 52 · see citing works
“…(Lukiw et al. 2012) 2 miR-33 AD ABCA1 miRNA overexpression cause Aβ toxicity and genetic deletion or inhibition results in reduced Aβ levels (Kim et al. 2015) 3 miR-34a AD TREM2 miRNA upregulation leaders to downregulation of TREM2 that is associated with inflammatory neurodegeneration…”
Background
MicroRNA-33a-5p sponges to inhibit pancreatic β-cell function in gestational diabetes mellitus LncRNA DANCR
Feng, Y., Qu, X., Chen, Y., Feng, Q., Zhang, Y., Hu, J., & Li, X. (2020) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-020-00618-8 · Cited by 46 · see citing works
“Similarly, multiple papers reported that miR-33a-5p targets ABCA1 in atherogenesis [18], morbidly obese [19], and brain [20].”
Background
Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease
Campos-Peña, V., Pichardo-Rojas, P., Sánchez-Barbosa, T., Ortíz-Islas, E., Rodríguez-Pérez, C., Montes, P., Ramos-Palacios, G., Silva-Adaya, D., Valencia-Quintana, R., Cerna-Cortés, J. F., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012092 · Cited by 41 · see citing works
Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41 · see citing works
“MicroRNA-33 (miR-33) has been shown to regulate ABCA 1 levels and ApoE lipidation in the brain, and antisense oligonucleotides specifically inhibit miR-33 in the brain, significantly reducing Aβ plaques in the cortex (Jana et al., 2008; Kim et al., 2015).”
Background
MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review
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TREM2 Alleviates Neuroinflammation and Improves Neurogenesis in ApoE−/− Mice by Regulating M1/M2 Microglial Polarization
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Authors: Kim, J., Yoon, H., Horie, T., Burchett, J. M., Restivo, J. L., Rotllan, N., Ramírez, C. M., Verghese, P. B., Ihara, M., Hoe, H.-S., Esau, C., Fernández-Hernando, C., Holtzman, D. M., Cirrito, J. R., Ono, K., & Kim, J.
Affiliations: Mayo Clinic (US)
Kyoto University (JP)
Washington University in St. Louis (US)
Yale University (US)
National Cerebral and Cardiovascular Center (JP)
Georgetown University Medical Center (US)
Regulus Therapeutics (United States) (US)
ORCID: Kim, Jaekwang
Yoon, Hyejin
Horie, Takahiro
Ramírez, Cristina M.
Verghese, Philip B.
Ihara, Masafumi
Esau, Christine
Holtzman, David M.
Cirrito, John R.
Ono, Koh
Kim, Jungsu
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2015-11-04
Volume: 35
Issue: 44
Pages: 14717-14726
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.2053-15.2015
PMC: PMC4635126
OpenAlex: W2204892940
Cited by: 128
References: 41
Citations by year: 2026: 5 · 2025: 8 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 22 · 2020: 14 · 2019: 11 · 2018: 13 · 2017: 10 · 2016: 11
FWCI: 7.30
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
PubMed Central (submittedVersion)
Funders: BrightFocus Foundation (A2012421, A2010613)
GHR Foundation
National Institutes of Health (5p50ag005681-36, 5p30ns069329-02, 5p50ag016574-20)
Center for Individualized Medicine, Mayo Clinic
Japan Society for the Promotion of Science (15H04271)
National Institute on Aging (AG039708, AG042513, AG016574, P50‐AG005681, P50‐AG016574, R01AG042513, R01 AG013956, R03 AG039708, R37AG013956, AG13956, AG005681)
National Heart, Lung, and Blood Institute (R01HL107953, HL107953)
National Institute of Neurological Disorders and Stroke (P30-NS069329, NS069329)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: microRNA-33, apolipoprotein E, amyloid-beta metabolism, ABCA1, Alzheimer's disease, cholesterol efflux, brain lipid metabolism, antisense oligonucleotides, APP/PS1 mice, amyloid-beta clearance, blood-brain barrier
MeSH terms: Animals, Apolipoproteins E, Base Sequence, Brain, Humans, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Amyloid beta-Peptides, Mice, Knockout, MicroRNAs, Lipid Metabolism, Mice

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microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain

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