Alzheimer's disease is the most common cause of dementia, a brain disorder that impairs cognitive function, and interferes with daily life. While certain problems in the brain have long been associated with the disease, the causes are still debated, and it has been very challenging to create effective treatments.
When Alzheimer’s disease was first identified by Alois Alzheimer in 1907, fat deposits, or "adipose saccules" were one of the things the doctor noticed and described. While these lipids were notable, there were other features like amyloid plaques and tau tangles in the brain that would become the primary focus of subsequent research on the disease. But a new study has highlighted the lipid pathology aspect of Alzheimer's brains, however, and has suggested that cells in the brain called microglia can become disrupted by lipid droplets, leading to tau tangles and neuronal death. Microglia are the brain's primary form of immune defense. The work has been reported in Nature.
This research may help explain why therapeutics that are aimed at amyloid plaques and tau tangles have not shown much success in patients. It is also supported by previous work indicating that the most significant genetic risk factors for Alzheimer's disease involve genes that are related to innate immunity, and the processing of lipids. The study has also linked the accumulation of lipid droplets to the most common Alzheimer's risk gene, a variant known as APOE4.
In Alzheimer's disease patients, the APOE gene is expressed at abnormally high levels in microglia. The APOE gene encodes for a protein that aids in the movement of fat in and out of cells. Variants of this gene include APOE2, APOE3, and APOE4. The APOE4 variant is known to be a significant risk factor for Alzheimer's disease.
In this work, the investigators performed single-cell sequencing on cells from patients with two copies of the APOE4 variant, or carriers with two copies of APOE3. People with the APOE4 variant were found to carry higher levels of an enzyme that is associated with lipids, called ACSL1 in their microglia.
The scientists also engineered microglia from pluripotent stem cells that were derived from carriers of the two genotypes. When microglial cells with two copies of APOE4 were then exposed to amyloid beta, a buildup of lipid droplets was triggered in the cells.
In additional work, microglia that contained lipid droplets were grown in culture, and the cell culture media was harvested from these cells. This media was then applied to neurons, which led to the development of tau tangles and neurotoxicity.
Lipid droplets themselves have been shown to be generated in myeloid cells due to an increase in innate immune activity, which can be in response to bacterial infection. Lipid droplets have some antimicrobial properties, and may be part of the innate immune response.
These lipids may also present a new target for Alzheimer's treatments, first study author Michael Haney of the University of Pennsylvania told New Scientist.
Sources: National Institute on Aging, Nature