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Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs
Abstract
The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.
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“Finally, in neurons, PCSK9 overexpression led to a worsening of neurotoxicity induced by different aggregation forms of Aβ, which have previously been demonstrated to have toxic effects in these cells [31,52].”
From PCSK9 affects astrocyte cholesterol metabolism and reduces neuron cholesterol supplying in vitro: potential implications in Alzheimer’s disease (2022) · cites this paper as [31]
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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 2×
“Experiments on AD-like transgenic mice have demonstrated that silencing ABCA1 decreases the lipidation of apoE, increases the deposition of Aβ, and reduces drastically high-density lipoproteins’ (HDLs) levels in the brain parenchyma and in the cerebrospinal fluid (CSF) [8,9].”
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Cited by
Sorted by citations
Papotti, B., Adorni, M. P., Marchi, C., Zimetti, F., Ronda, N., Panighel, G., Lupo, M. G., Vilella, A., Giuliani, D., Ferri, N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012192 · Cited by 41
Metadata
- Authors
- Sierri, G., Dal Magro, R., Vergani, B., Leone, B. E., Formicola, B., Taiarol, L., Fagioli, S., Kravicz, M., Tremolizzo, L., Calabresi, L., & Re, F.
- Affiliations
- BioNanoMedicine Center NANOMIB, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
- Department of Pharmacological and Biomolecular Science, Centro Grossi Paoletti, University of Milan, 20133 Milan, Italy
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-12-22
- Volume
- 23
- Issue
- 1
- Pages
- 102
- ISSN
- 1422-0067
- PMC
- PMC8745016
- Cited by
- 16
- References
- 2
- Language
- en
- Funders
- PRIN Research Italy (2017PFYK27)
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