Direct intracerebral delivery of a miR-33 antisense oligonucelotide into mouse brain increases brain ABCA1 expression
Abstract
The ATP-binding cassette transporter A1 (ABCA1) is a membrane bound protein that serves to efflux cholesterol and phospholipids onto lipid poor apolipoproteins during HDL biogenesis. Increasing the expression and activity of ABCA1 have beneficial effects in experimental models of various neurologic and cardiovascular diseases including Alzheimer's disease. Despite the beneficial effects of liver X receptor (LXR) agonists--compounds that increase ABCA1 expression--in preclinical studies, their therapeutic utility is limited by systemic adverse effects on lipid metabolism. Interestingly, microRNA-33 (miR-33) inhibition increases ABCA1 expression and activity in rodents and non-human primates without severe metabolic adverse effects. Herein, we demonstrate that treatment of cultured mouse neurons, astrocytes and microglia with an antisense oligonucleotide (ASO) targeting miR-33 increased ABCA1 expression, which was accompanied by increased cholesterol efflux and apoE secretion in astrocytic cultures. We also show that intracerebral delivery of an ASO targeting miR-33 leads to increased ABCA1 expression in cerebral cortex or subcortical structures such as hippocampus. These findings highlight an effective strategy for increasing brain ABCA1 expression/activity for relevant mechanistic studies. [Corrected]
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 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 [18]
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 [18]
Pharmacological inhibition of miR-33 significantly increases ABCA1 level.
“pharmacological inhibition of miR-33 significantly increased ABCA1 level [127, 128].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [128]
Cites
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 · see citing works
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 · see citing works
Central nervous system: cholesterol turnover, brain development and neurodegeneration
Dietschy, J. M. (2009) · bchm · doi:10.1515/bc.2009.035 · Cited by 394 · see citing works
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 · see citing works
Koldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411420200 · Cited by 279 · see citing works
Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis
Brunham, L. R., Singaraja, R. R., Duong, M., Timmins, J. M., Fievet, C., Bissada, N., Kang, M. H., Samra, A., Fruchart, J.-C., McManus, B., et al. (2009) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.182303 · Cited by 102 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
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
MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease
Yoon, H., Flores, L. F., & Kim, J. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.04.020 · Cited by 23 · see citing works
Tate, M., Wijeratne, H. R. S., Kim, B., Philtjens, S., You, Y., Lee, D., Gutierrez, D. A., Sharify, D., Wells, M., Perez‐Cardelo, M., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14243 · Cited by 16 · see citing works
“17,18 Although the significance of ABCA1 overexpression in amyloid pathology has been demonstrated in a mouse model, 13 there was a lack of human data linking ABCA1 to an increased risk of developing AD.”
- Authors
- Jan, A., Karasinska, J. M., Kang, M. H., de Haan, W., Ruddle, P., Kaur, A., Connolly, C., Leavitt, B. R., Sorensen, P. H., & Hayden, M. R.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Hayden, Michael R.
- ORCID
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 598
- Pages
- 66-72
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W324662074
- Cited by
- 28
- References
- 6
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 4 · 2016: 7 · 2015: 1
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-08-18)
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Alzheimer Society of Canada
- Pfizer Canada Ripples of Hope
- Canadian Institute of Health Research
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- miR-33, antisense oligonucleotides, ABCA1, cholesterol efflux, astrocytes, microglia, neurons, HDL biogenesis, liver X receptor agonist, Alzheimer's disease, cerebral cortex, hippocampus
- MeSH terms
- Animals, Apolipoproteins E, Astrocytes, Brain, Cell Line, Cholesterol, Injections, Intraventricular, Mice, Inbred C57BL, Neurons, Oligonucleotides, Antisense, Microglia, MicroRNAs, Mice, Primary Cell Culture, ATP Binding Cassette Transporter 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
