The ability of brain cells to take in substances from their surface is essential to the production of a key ingredient in Alzheimer’s brain plaques, School of Medicine neuroscientists have learned.
The researchers used a drug to shut down the intake process, known as endocytosis, in a mouse model of Alzheimer’s disease. The change led to a 70 percent drop in levels of amyloid beta, the protein fragment that clumps together to form Alzheimer’s plaques. Importantly, they also found that the ability of endocytosis to increase amyloid beta was coupled to normal nerve cell communication.
“Blocking endocytosis isn’t a viable option for treatment because cells throughout the body, including brain cells, need endocytosis for healthy function,” said first author John Cirrito, Ph.D., research instructor in neurology. “But we are starting to understand the origins of amyloid beta in more detail now, and what we’re learning is opening other options we can pursue to seek new treatments for Alzheimer’s disease.”
While endocytosis is necessary for normal function of brain cells, Cirrito and others believe it may accidentally be causing the cells to take in the amyloid precursor protein (APP), which breaks down into amyloid beta. If so, a drug that reduces brain cells’ intake of APP may help reduce amyloid beta production.
The results appeared in the April 10 issue of Neuron.
Previous research had shown that endocytosis might be important for amyloid beta production and that amyloid beta is produced inside brain cells. In 2005, Cirrito and his colleagues linked increased communication between brain cells to higher amyloid beta levels.
Cirrito decided to test endocytosis and brain cell activity in a coordinated fashion. He used microdialysis, a technique that he had previously adapted for Alzheimer’s research, to monitor the results.
In addition to allowing repeated sampling of the amyloid beta levels in the brains of live mice, the approach allows him to introduce drugs that reduce endocytosis and alter communication between brain cells.
When researchers gave mice the drug that stopped endocytosis, amyloid beta levels dropped by 70 percent. To see how much normal brain activity contributed to ongoing amyloid beta production in the absence of endocytosis, they then added a second drug that reduced brain cell communication. Amyloid beta levels did not decrease further.
When they reversed the experiment, reducing brain cell communication first, amyloid beta decreased by 60 percent. Adding the drug that stops endocytosis caused an additional small reduction in amyloid beta.
The results show that amyloid beta production requires both brain cell communication and endocytosis, but endocytosis is essential for a slightly larger share of amyloid beta.
Cirrito conducted the research in the laboratories of co-senior authors David M. Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital; and Steven J. Mennerick, Ph.D., associate professor of neurobiology and psychiatry.