The APOE4 Gene Disrupts Endocytosis, But The PICALM Gene Can Negate That Defect

From MIT News by Picower Institute for Learning & Memory at MIT and The Whitehead Institute for Biomedical Research

Some definitions are needed before we begin. Astrocytes are star-chaped non-neuronal cells in the central and peripheral nervous system that support the neurons by maintaining balance of nutrients and chemicals that neurons need. In the research here, the astrocytes were derived from stem cells.

Endocytosis is the taking in of key particles, or molecules, into a cell by invaginating or indenting around the particle, forming a pocket around the targeted particle.

The APOE gene provided the instructions for making apolipoprotein E, a protein that combines with lipids to form a compound responsible for carrying cholesterol and other fats through the bloodstream. A variant of this gene, APOE4, has been found to be an Alzheimer’s risk gene (late onset after 65 years of age). Close to 25% of the general population have one copy of this gene, which increases their chance of developing Alzheimer’s. If they have two copies, it increases their chance even more and they can develop Alzheimer’s before age 65. APOE3 is the normal gene that most people carry and doesn’t influence AD, and APOE2 is a variant that seems to be somewhat protective from getting Alzheimer’s disease.

The PICALM gene is also an Alzheimer’s risk gene, that somehow effects the beta-amyloid protein. It is also suspect in a number of other diseases.

Astrocytes help communication between neurons by maintaining the homeostasis for those cells. Those astrocytes that possess the APOE4 gene have impaired communication and are unable to maintain the metabolic needs of the cells they are supposed to help. The scientists here engineered yeast cells with APOE4 and APOE3 genes. What they found was that those with the APOE4 cells showed impaired homeostasis, but those with the APOE3 gene did not (the gene that most people carry). Somehow increasing the expression of the PICALM gene (in the yeast cell this gene is called Yap1802p) reversed the effects of the bad APOE4 gene!

Yes, the study was done in yeast cells, and studies don’t always correlate when done in humans, but this is tremendous news. It provides future avenues of study to see if the same is true when in the human body. Then if they could discover or make a drug that excites the PICALM gene to turn off the negative effects of APOE4 we might have something that works for the Alzheimer’s Disease population. Doing the same in a cell with APO3, however, showed negative effects, so this PICALM or Yap1802p gene reacts differently depending on surrounding factors!

Since no cure has been found so far in all the years of research, this gene approach provides some hope that something might be discovered in our lifetime as a treatment. This renews our hope!

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