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

Dustin Chernick, Stephanie Ortiz-Valle, Angela Jeong, Suresh Kumar Swaminathan, Karunya K Kandimalla, G. William Rebeck, Ling Li

Research output: Contribution to journalArticle

3 Citations (Scopus)

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. (Figure presented.). Read the Editorial Highlight for this article on page 580.

Original languageEnglish (US)
Pages (from-to)647-662
Number of pages16
JournalJournal of Neurochemistry
Volume147
Issue number5
DOIs
StatePublished - Dec 1 2018

Fingerprint

Microglia
Apolipoproteins E
HDL Lipoproteins
Amyloid
Astrocytes
Alzheimer Disease
Neuroglia
Brain
Apolipoprotein E4
Lipids
apolipoprotein A-I mimetic peptide 4F
Inhibition (Psychology)
Serum Amyloid A Protein
ATP-Binding Cassette Transporters
Secretory Pathway
Golgi Apparatus
Endoplasmic Reticulum
Dementia
Agglomeration
Genes

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia. / Chernick, Dustin; Ortiz-Valle, Stephanie; Jeong, Angela; Swaminathan, Suresh Kumar; Kandimalla, Karunya K; Rebeck, G. William; Li, Ling.

In: Journal of Neurochemistry, Vol. 147, No. 5, 01.12.2018, p. 647-662.

Research output: Contribution to journalArticle

Chernick, Dustin ; Ortiz-Valle, Stephanie ; Jeong, Angela ; Swaminathan, Suresh Kumar ; Kandimalla, Karunya K ; Rebeck, G. William ; Li, Ling. / High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia. In: Journal of Neurochemistry. 2018 ; Vol. 147, No. 5. pp. 647-662.
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AU - Chernick, Dustin

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AU - Jeong, Angela

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AU - Rebeck, G. William

AU - Li, Ling

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AB - 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. (Figure presented.). Read the Editorial Highlight for this article on page 580.

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