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J Neurochem. 2018 Dec;147(5):647-662. doi: 10.1111/jnc.14554. Epub 2018 Nov 26.

High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia.

Author information

1
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
2
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
3
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA.
4
Department of Neuroscience, Georgetown University, Washington, District of Columbia, USA.
5
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.

Abstract

The apolipoprotein E (apoE) ε4 allele is the primary genetic risk factor for late-onset Alzheimer's disease (AD). ApoE in the brain is produced primarily by astrocytes; once secreted from these cells, apoE binds lipids and forms high-density lipoprotein (HDL)-like particles. Accumulation of amyloid-β protein (Aβ) in the brain is a key hallmark of AD, and is thought to initiate a pathogenic cascade leading to neurodegeneration and dementia. The level and lipidation state of apoE affect Aβ aggregation and clearance pathways. Elevated levels of plasma HDL are associated with lower risk and severity of AD; the underlying mechanisms, however, have not been fully elucidated. This study was designed to investigate the impact of an HDL mimetic peptide, 4F, on the secretion and lipidation of apoE. We found that 4F significantly increases apoE secretion and lipidation in primary human astrocytes as well as in primary mouse astrocytes and microglia. Aggregated Aβ inhibits glial apoE secretion and lipidation, causing accumulation of intracellular apoE, an effect that is counteracted by co-treatment with 4F. Pharmacological and gene editing approaches show that 4F mediates its effects partially through the secretory pathway from the endoplasmic reticulum to the Golgi apparatus and requires the lipid transporter ATP-binding cassette transporter A1. We conclude that the HDL mimetic peptide 4F promotes glial apoE secretion and lipidation and mitigates the detrimental effects of Aβ on proper cellular trafficking and functionality of apoE. These findings suggest that treatment with such an HDL mimetic peptide may provide therapeutic benefit in AD. Read the Editorial Highlight for this article on page 580.

KEYWORDS:

Alzheimer's disease; HDL mimetic peptide; amyloid-β; apolipoprotein E; astrocytes and microglia; lipidation

PMID:
30028014
PMCID:
PMC6314045
DOI:
10.1111/jnc.14554
[Indexed for MEDLINE]
Free PMC Article

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