At the turn of the 20th century, Dr. Alois Alzheimer noticed peculiar changes in a freshly removed brain. The brain had belonged to a 50-year-old woman who gradually lost her memory and struggled with sleep, increased aggression, and eventually paranoia.
Under the microscope, her brain was littered with tangles of protein clumps. 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. Instead, the fatty pouches built up in supporting brain cells called glia.
Scientists have long thought toxic protein clusters lead to or exacerbate Alzheimer’s disease. Decades of work aimed at breaking down these clumps has mostly failed—earning the endeavor the nickname “graveyard of dreams.” There has been a recent win. In early 2023, the US Food and Drug Administration approved an Alzheimer’s drug that slightly slowed cognitive decline by inhibiting protein clumps, although amid much controversy over its safety.
A growing number of experts are exploring other ways to battle the mind-eating disorder. 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. Those who did harbored a specific variant of a gene, called APOE4. Scientists have long known that APOE4 increases the risk of Alzheimer’s, but the reason why has remained a mystery.
The fatty bubbles may be the answer. Lab-made microglia cells from people with APOE4 rapidly accumulated bubbles and spewed them onto neighboring cells. When treated with liquids containing the bubbles, healthy neurons developed classical signs of Alzheimer’s disease.
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.
“This opens up a new avenue for therapeutic development,” the University of Pennsylvania’s Dr. Michal Haney, who was not involved in the study, told New Scientist.
The Forgetting Gene
Two types of proteins have been at the heart of Alzheimer’s research.
One is beta-amyloid. These proteins start as wispy strands, but gradually they grasp each other and form large clumps that gunk up the outside of neurons. Another culprit is tau. Normally innocuous, tau eventually forms tangles inside neurons that can’t be easily broken down.
Together, the proteins inhibit normal neuron functions. Dissolving or blocking these clumps should, in theory, restore neuronal health, but most treatments have shown minimal or no improvement to memory or cognition in clinical trials.
Meanwhile, genome-wide studies have found a gene called APOE is a genetic regulator of the disease. It comes in multiple variants: APOE2 is protective, whereas APOE4 increases disease risk up to 12-fold—earning its nickname the “forgetting gene.” Studies are underway to genetically deliver protective variants that wipe out the negative consequences of APOE4. Researchers hope this approach can halt memory or cognitive deficits before they occur.
But why are some APOE variants protective, while others are not? Fatty bubbles may be to blame.
Cellular Gastronomy
Most cells contain little bubbles of fat. Dubbed “lipid droplets,” they’re an essential energy source. 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.
APOE is a major gene regulating these lipid droplets. 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. Some had the dangerous APOE4 variant; others had APOE3, which doesn’t increase disease risk. In all, the team analyzed roughly 100,000 cells—including neurons and myriad other brain cell types, such as the immune cell microglia.
Comparing results from the two genetic variants, the team found a stark difference. People with APOE4 had far higher levels of an enzyme that generates lipid droplets, but only in 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. In a standard cognitive test in mice, more lipid droplets correlated to worse performance. 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.
Although the droplets accumulated inside microglia, they also readily harmed nearby neurons.
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.
They then gathered secretions from microglia with either high or low levels of lipid droplets and treated the engineered neurons with the liquids. Secretions with low levels of fatty bubbles didn’t harm the cells. But neurons given doses high in lipid droplets rapidly changed tau—a classic Alzheimer’s protein—into its disease-causing form. Eventually, these neurons died off.
This isn’t the first time fatty bubbles have been linked to Alzheimer’s disease, but we now have a clearer understanding of why. 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.
One route is to genetically inhibit the enzyme that creates the lipid droplets in APOE4 microglia. 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. It’s a well-known strategy that’s previously been used to destroy toxic protein clumps, but it could be reworked to clear out lipid droplets.
“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.
As a next step, they’re exploring whether the protective APOE2 variant can thwart lipid droplet accumulation in microglia, and perhaps, eventually save the brain’s memory and cognition.
Image Credit: Richard Watts, PhD, University of Vermont and Fair Neuroimaging Lab, Oregon Health and Science University
