Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer’s Disease (LOAD)

TL;DR

Astrocytes from Alzheimer's patients show reduced cholesterol esters and fatty acids, suggesting these lipid changes may be early signs of the disease.

Contribution

Identifies inherent lipid abnormalities in astrocytes as potential precursors to late-onset Alzheimer’s disease.

Findings

Astrocytes from LOAD patients show substantial reductions in cholesterol esters.

Most fatty acids in membrane lipids, including mitochondrial membranes, are reduced in LOAD astrocytes.

Lipid abnormalities are inherent and may serve as early targets for intervention.

Abstract

What are the main findings?
There are substantial reductions in cholesterol esters in astrocytes derived from cells of patients with late-onset Alzheimer’s disease (LOAD).Most fatty acids in membrane lipids of these astrocytes, including in mitochondrial membranes, tend to be reduced, with only a few increased.

There are substantial reductions in cholesterol esters in astrocytes derived from cells of patients with late-onset Alzheimer’s disease (LOAD).

Most fatty acids in membrane lipids of these astrocytes, including in mitochondrial membranes, tend to be reduced, with only a few increased.

What are the implications of the main findings?
Because these astrocytes are derived from induced pluripotent stem cell (iPSC) lines, the abnormalities observed are inherent features of the cells and may be the determinants of LOAD.These abnormalities may be targets for interventions that would reduce the risk for LOAD or slow its progression.

Because these astrocytes are derived from induced pluripotent stem cell (iPSC) lines, the abnormalities observed are inherent features of the cells and may be the determinants of LOAD.

These abnormalities may be targets for interventions that would reduce the risk for LOAD or slow its progression.

Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer’s disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.

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