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.
Bibliographical noteFunding Information:
This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (AG056025, AG056976, and AG058081), the National Institute of Neurological Disorders and Stroke (NS100704), and the Center on Aging and the Academic Health Center of the University of Minnesota. DC is supported by a predoctoral training fellowship in the PharmacoNeuroImmunol-ogy Program from the National Institute on Drug Abuse of the National Institutes of Health (T32DA007097) and a 3M Science and Technology Training Fellowship. We would like to thank Drs. Shuxian Hu and James Lokensgard for their training in the collection and culturing of primary mouse glial cells. We also would like to thank Drs. Mary Jo LaDu and Leon Tai for providing the synthetic Aβ and Dr. Guojun Bu for providing human apoE targeted replacement immortalized mouse astrocytes and the antibody against LRP1. In addition, we thank Dr. Wei Zhang for her assistance in characterization of Aβ preparations by transmission electron microscopy in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. The authors have no conflicts of interest to disclose.
- Alzheimer's disease
- HDL mimetic peptide
- apolipoprotein E
- astrocytes and microglia