The protein and lipid compositions of brain apolipoprotein E particles are cell type-specific
Genetic variation in APOE, which encodes a lipid transporter apolipoprotein E (apoE), is the strongest risk factor for late-onset Alzheimer's disease (AD). Although central nervous system (CNS) apoE is produced by various cell types, including astrocytes, microglia, and pericytes, it is unclear whether apoE lipoproteins are a homogeneous population or if their molecular composition varies…
Apolipoprotein E (apoE) is a lipid transporter encoded by the APOE gene, which plays a significant role in Alzheimer's disease (AD) risk. Although various central nervous system (CNS) cell types produce apoE, the molecular composition of their apoE lipoproteins remains unclear. Recent findings indicate that the composition of apoE lipoproteins varies depending on their cellular origin and contributes to AD-related processes in a cell type-specific manner.
To investigate this, researchers hypothesized that the lipid and protein profiles of apoE particles depend on their cellular origin and examined the profiles of apoE particles from induced pluripotent stem cell (iPSC)-derived brain cells and human cerebrospinal fluid (CSF) using liquid chromatography-mass spectrometry (LC-MS/MS).
The results showed that astrocytes, pericytes, and microglia secrete apoE lipoproteins with distinct lipid and protein profiles. Astrocyte-secreted particles had higher levels of sphingomyelins and proteins related to lipid metabolism, while pericyte-secreted particles contained ether-linked phospholipids and proteins associated with antioxidant activity.
Microglial apoE particles had lower lipidation but higher levels of transferrin, apoC-II, and cathepsin D. One-third of the identified features were cell type-specific, underscoring the molecular specialization among cell types. Most lipids and proteins found in cell-secreted apoE were also present in CSF-derived particles. This study provides new insights into apoE biology, shifting the focus from apoE as a single entity to a diverse population of complex particles whose composition may influence functions in health and neurodegenerative diseases.
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