The Role of Astrocyte-Derived Cholesterol in Alzheimer’s Disease

Post by Ifrah Khanyaree

What's the science?

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aß) plaques in the brain and cognitive impairment. AD is estimated to affect over 20 million people worldwide. This week in PNAS, Wang and colleagues used super-resolution imaging to show that astrocyte cholesterol synthesis and its transport controls Aß accumulation and hence plaque formation in AD.                                                

How did they do it?

For the first experiment, the authors wanted to establish astrocytes as a key cholesterol source. They took a control cell culture and looked at a specific lipid cluster. They compared the size of this lipid cluster to the size of the same lipid cluster in neurons co-cultured with cholesterol-deficient astrocytes. As a second experiment, to establish the integral role of Apolipoprotein E, apoE (which is a cholesterol transport protein produced by astrocytes), they compared two cultures of cells — one loaded with apoE and a cholesterol source and the other only with apoE.

Next, the authors wanted to confirm whether astrocytes directly control Aβ peptide production (which leads to Aβ plaques). For this, only neurons were isolated from other cortical cells in one culture and, for a second mixed culture, both neurons and astrocytes were used. These cell cultures were treated with or without apoE, labelled, and then imaged with super-resolution microscopy. Finally, to confirm astrocyte-derived cholesterol as the regulator of amyloid precursor protein or APP (which generates Aß peptides) they knocked out the main transcriptional regulator of enzymes involved in cholesterol synthesis.

What did they find?

The authors found that without astrocyte derived cholesterol, the size of the lipid cluster in primary neurons was significantly smaller, suggesting that astrocytes are needed for the transport of cholesterol to neurons. This was confirmed in their second experiment, where they observed cells loaded with apoE and a cholesterol source increased in cluster diameter and those without cholesterol actually decreased in size as well as number.

They were also able to confirm the role of astrocytes in APP regulation and Aß production. The authors observed a decrease in APP and lipid cluster association in a cell culture containing only neurons and apoE. The opposite effect was seen in a mixed culture with astrocytes with neurons. There was a 2.5x increase in APP association with lipid clusters. This demonstrates that astrocytes are necessary for synthesizing the cholesterol that is then shuttled to neuronal membranes. The more cholesterol that is loaded into neuronal membranes, the more APP interacts with enzymes that cleave it to make Aß peptides. 

What's the impact?

This study found that astrocyte-derived cholesterol tightly regulates the formation of beta-amyloid plaques in AD. Before this, the role of astrocytes in AD pathogenesis was not well understood. In this study, Wang and colleagues establish a molecular pathway that defines the role of astrocytes in plaque formation by the production and distribution of cholesterol to neurons.

Wang et al. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. PNAS (2021). Access the original scientific publication here.