At the turn of the 20th century, Dr. Alois Alzheimer noticed peculiar changes in a freshly removed brain. Curiously, shiny bubbles of fat had also accumulated inside brain cells, but they weren’t neurons-the brain cells that spark with electricity and underlie our thoughts and memories. Scientists have long thought toxic protein clusters lead to or exacerbate Alzheimer’s disease. Stanford’s Dr. Tony Wyss-Coray thinks an answer may come from the original source; Alois Alzheimer’s first descriptions of fatty bubbles inside glia cells-but with a modern genetic twist. In a new study, the team targeted fatty bubbles as a potential driver of Alzheimer’s disease.
Using donated brain tissue from people with the disorder, they pinpointed one cell type that’s especially vulnerable to the fatty deposits-microglia, the brain’s main immune cells.
Not all people with Alzheimer’s had overly fatty microglia. Scientists have long known that APOE4 increases the risk of Alzheimer’s, but the reason why has remained a mystery.
Lab-made microglia cells from people with APOE4 rapidly accumulated bubbles and spewed them onto neighboring cells. The results uncover a new link between genetic risk factors for Alzheimer’s and fatty bubbles in the brain’s immune cells, the team wrote in their paper.
Cellular Gastronomy Most cells contain little bubbles of fat. The bubbles interact with other cellular components to control a cell’s metabolism.
Each bubble has a core of intricately arranged fats surrounded by a flexible molecular “Cling wrap.” Lipid droplets can rapidly grow or shrink in size to buffer toxic levels of fatty molecules in the cell and direct immune responses against infections in the brain.
The new study asked if fatty deposits are the reason APOE4 increases the risk of Alzheimer’s disease. The team first mapped all proteins in different types of cells in brain tissues donated from people with Alzheimer’s.
In all, the team analyzed roughly 100,000 cells-including neurons and myriad other brain cell types, such as the immune cell microglia.
The droplets collected around the nucleus-which houses our genetic material-similar to Alois Alzheimer’s first description of fatty deposits.
The lipid droplets also increased the levels of dangerous proteins in Alzheimer’s disease, including amyloid and tau.
Like humans, mice with the APOE4 variant had far more fatty microglia than those with the “Neutral” APOE3, and the immune cells had higher levels of inflammation.
In a test, the team transformed skin cells from people with APOE4 into a stem cell-like state. With a specific dose of chemicals, they nudged the cells to develop into neurons with the APOE4 genotype. Secretions with low levels of fatty bubbles didn’t harm the cells. Neurons given doses high in lipid droplets rapidly changed tau-a classic Alzheimer’s protein-into its disease-causing form.
Lipid droplets accumulate in microglia with APOE4, transforming these cells into an inflammatory state that harms nearby neurons-potentially leading to their death.
The study adds to recent work highlighting irregular immune responses in the brain as a major driver of Alzheimer’s and other neurodegenerative diseases.
It’s yet unclear whether lowering lipid droplet levels can relieve Alzheimer’s symptoms in people with APOE4, but the team is eager to try.
Another option is to use drugs to activate the cell’s built-in disposal system-basically, a bubble full of acid-to break down the fatty bubbles.
“Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation potentially providing therapeutic strategies for Alzheimer’s disease,” wrote the team in their paper.