Apoe4 Affects Lipid Pathways in the Brain

[Plumster]

Abstract

APOE4 is the strongest genetic risk factor for Alzheimer’s disease1,2,3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4,5,6,7,8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2,3,4,5,6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease.

Access to full article in Nature here

It seems that statins (simvastatin and atorvastatin) are what help facilitate cholesterol transport in the brain and increasing myelination.

[Lulu]

Hi Plumster,

Zuben47 recently posted an article entitled "Alzheimer's APOE4 Impairs Myelination through Cholesterol Dysregulation" I was really encouraged after reading the article, which stated:


"The team focused on drugs that affect cholesterol including statins (which suppress synthesis) and cyclodextrin, which aids cholesterol transport. The statins did not have an effect, but applying cyclodextrin to APOE4 oligodendrocyte cultured in a dish reduced accumulation of cholesterol within the cells and improved myelination in co-cultures with neurons. It showed similar effects in APOE4 mice.

Finally, the team treated some APOE4 mice with cyclodextrin, left others untreated, and subjected them all to two different memory tests. The cyclodextrin-treated mice performed both tests significantly better, suggesting an association between improved myelination and improved cognition."


I looked up cyclodextrin, its an oligosaccharide, and I'm not sure if you can buy it. However, there are various oligosaccharides available as prebiotic supplements, and have benefits that would definitely appear to be great for the APOE4 community. Here is some great information about Xylooligosaccharide (XOS)


https://www.ncbi.nlm.nih.gov/pmc/articl ... )%20levels.


My recent labs showed an elevated ldl, and I'm waking in the middle of the night again, so I'm hoping this prebiotic may help. XOS has been shown to decrease ldl, and increase butyric acid, which could be beneficial for both my current issues.

[Plumster]

Thank you for the info, Lulu. I think it may be the same research, as this article also addresses the benefits of cyclodextrin. I was not aware of the prebiotic or its effects. That's definitely some good news.