title: Direct intracerebral delivery of a miR-33 antisense oligonucleotide into mouse brain increases brain ABCA1 expression. [Corrected].
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]
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Asad
authors.initials: A
authors.lastname: Jan
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Karasinska
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Willeke
authors.initials: W
authors.lastname: de Haan
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Piers
authors.initials: P
authors.lastname: Ruddle
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Achint
authors.initials: A
authors.lastname: Kaur
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Colum
authors.initials: C
authors.lastname: Connolly
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.affiliation: BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Electronic address: mrh@cmmt.ubc.ca.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D061251:Primary Cell Culture
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002784:Cholesterol; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; C577833:Abca1 protein, mouse; C550417:Mirn33 microRNA, mouse
keywords: ABCA1; Alzheimer’s disease; Antisense oligonucleotides; Intracerebral infusion; MicroRNA-33