Revitalizing mitochondria to treat Alzheimer’s disease

Nerve cells in the brain require an enormous amount of energy to survive and maintain their connections to communicate with other nerve cells. In Alzheimer’s disease, the ability to produce energy is compromised and the connections between nerve cells (called synapses) eventually disintegrate and wither, causing new memories to disappear and fail.

A team from Scripps Research, reporting in the journal Advanced science, has now identified the energetic reactions in brain cells that malfunction and lead to neurodegeneration. Using a small molecule to address dysfunction in mitochondria, the cell’s primary energy producers, researchers showed that many neuron-to-neuron connections were successfully restored in nerve cell models derived from human stem cells. human patients with Alzheimer’s disease. These results highlight that improving mitochondrial metabolism could constitute a promising therapeutic target for Alzheimer’s disease and related disorders.

“We thought that if we could repair the metabolic activity in the mitochondria, we might be able to rescue energy production,” says lead author Stuart Lipton, M.D., Ph.D., Step Endowed Professor. Family Foundation and co-director of the NeurodeGeneration New Medicines program. Scripps Research Center and clinical neurologist in La Jolla, California. “Using human neurons derived from people with Alzheimer’s disease, the protection of energy levels was sufficient to rescue a large number of neuronal connections.”

In the new study, Lipton and his team discovered a blockage in enzymes that produce energy due to an abnormal labeling of nitrogen (N) and oxygen (O) atoms on a sulfur atom (S), all together forming a dysfunctional “SNO”. enzyme. This reaction is called S-nitrosylation, and the team demonstrated that a virtual “SNO storm” of these reactions occurred in neurons in the Alzheimer’s brain.

Lipton and his colleagues initially discovered the “SNO-tag” on energy enzymes by comparing human brains (obtained from autopsies of people with Alzheimer’s disease) to those without brain disease. The researchers then generated nerve cells from stem cells derived from skin biopsies of people with or without a genetic mutation that causes Alzheimer’s disease. Then, using a series of metabolic markers and an oxygen measuring device, they calculated cellular energy production and identified unique deficits in Alzheimer’s disease nerve cells by report to witnesses.

The researchers found that the neurons exhibited a disrupted Krebs cycle, the cellular process in mitochondria that produces most of the body’s crucial molecular energy source, ATP. The team identified a bottleneck (or blockage) in the formation step of a key molecule: succinate, which determines a large part of the subsequent production of ATP. In the study, the bottleneck inhibited the ability of mitochondria to produce the energy needed to maintain neurons and their many connections.

The researchers hypothesized that if they could supply some of the missing succinate molecules, they might be able to restore energy production, which would essentially restart the stalled mitochondrial Krebs cycle. Since succinate does not travel easily in or out of cells, they used an analog that could better cross nerve cell membranes. The strategy worked, repairing up to three-quarters of the lost synapses, while preventing further decline.

“Succinate is not a compound that people can now take as a treatment, but it is proof of principle that you can reinvigorate the Krebs cycle,” Lipton says. “The beauty of the study is that we were able to show it in living nerve cells derived from Alzheimer’s patients, but we still need to find a much better compound in order to develop an effective drug for humans to take .”

Lipton has a history of developing FDA-approved drugs for Alzheimer’s disease, such as Namenda, and recognizes that much more work is needed here to produce an additional energy-saving drug that is both safe and effective in the man. His lab will continue to study the mitochondrial Krebs cycle as a promising therapeutic target in hopes of being able to restore neuronal connectivity in Alzheimer’s disease patients, thereby halting disease progression and improving cognitive function.

In addition to Lipton, study authors include Alexander Andreyev, Nima Dolatabadi, Xu Zhang, Melissa Luevanos, Mayra Blanco, Christine Baal, Ivan Putra and Tomohiro Nakamura of Scripps Research; Hongmei Yang and Steven Tannenbaum of MIT; and Paschalis-Thomas Doulias and Harry Ischiropoulos of the Perelman School of Medicine at the University of Pennsylvania.