Summary: Stem cell study reveals astrocytes carrying the Alzheimer’s associated APOE4 gene release more cholesterol than those carrying the APOE3 gene. Findings shed light on how different versions of the APOE gene in astrocytes influence amyloid-beta production and how the oversupply of cholesterol associated with APOE4 astrocytes may promote amyloid-beta formation in Alzheimer’s patients.
AD, the most frequent cause of dementia, affects an estimated 24 million people worldwide. With very limited treatment options, scientists are looking for ways to understand the disease better.
One hallmark of AD is the emergence of so-called beta-amyloid plaques, clumps of beta-amyloid protein accumulating in the brain and thought to be toxic to adjacent neurons. The causes for Alzheimer’s disease and the formation of beta-amyloid plaques are still largely unknown but genetic studies found that a gene called APOE, which is involved in cholesterol metabolism and transport, is linked to AD in the elderly.
The APOE gene exists in different versions in people, APOE2, APOE3 and APOE4, but the APO4 gene comes with a relatively higher risk of developing AD.
Curiously, in the brain, it’s mostly the supporting cells called astrocytes rather than the neurons that make ApoE protein. To find out if the APOE4 gene in astrocytes relates to AD, Jinsoo Seo and colleagues with the Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea, used human-induced stem cells carrying different versions of the APOE gene to make neurons and astrocytes in the lab, and to study their interaction.
The researchers found that astrocytes carrying the AD-associated APOE4 gene released more cholesterol than astrocytes with APOE3.
The scientists noticed that the neurons exposed to higher cholesterol had distinct changes to their cell membranes, the outer layers of the cell which normally contain cholesterol. Further, this high cholesterol content in cell membranes was directly related to the increased production and secretion of beta-amyloid by the neurons.
This work illustrates how different versions of the APOE gene in astrocytes can influence beta-amyloid production in neurons, and how cholesterol oversupply from ApoE4 astrocytes might promote the formation of toxic beta-amyloid plaques in AD patients.
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Author: Kwanghoon CHOI Source: DGIST Contact: Kwanghoon CHOI – DGIST Image: The image is in the public domain
ApoE4-carrying Human Astrocytes Oversupply Cholesterol into Neurons and Promote Aβ Generation
The onset of Alzheimer’s disease (AD) typically occurs later in life. Importantly, however, recent genetic analysis of patients and unaffected individuals revealed multiple genetic variants associated with late-onset AD. One of the strongest genetic risk factors for AD is 𝜀4 allele of APOE encoding apolipoprotein (ApoE), which is predominantly expressed in glial cells. One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as Aβ accumulation and neurodegeneration.
Here, we use human induced pluripotent stem cells (hiPSCs) from healthy individuals and isogenic cells in which the ApoE 𝜀3 allele was replaced with an 𝜀4 allele to generate human neurons and astrocytes. We then investigate the effect of astrocytic ApoE4 on the neuronal Aβ production.
We find that secretory factors in conditioned media from hiPSC-derived astrocytes carrying APOE4 significantly increased the levels of APP and Aβ secretion in hiPSC-derived neurons. Increasing cholesterol levels in culture media mimicked the effects of ApoE4 ACM by inducing the formation of lipid rafts that potentially provide a physical platform for APP localization on the membrane. We further found that reducing cholesterol levels in ApoE4 ACM with MβCD abolished its effects on neuronal lipid raft expansion and Aβ generation.
Our study suggests that ApoE4 astrocytes contribute to amyloidosis by the expansion of lipid rafts and facilitate neuronal Ab production through oversupply of cholesterol.