Scientists have made a groundbreaking discovery that could potentially reverse memory loss associated with neurodegenerative diseases. Researchers from Inserm and the University of Bordeaux, in collaboration with colleagues from the Université de Moncton in Canada, have successfully established a causal link between mitochondrial dysfunction and cognitive symptoms related to these conditions.

Mitochondria are tiny energy-producing structures within cells that provide the power needed for proper functioning. The brain is one of the most energy-demanding organs, relying on mitochondria to produce energy for neurons to communicate with each other. When mitochondrial activity is impaired, neurons fail to function correctly, leading to progressive neuronal degeneration and eventually, cell death.

In Alzheimer’s disease, for example, it has been observed that impaired mitochondrial activity precedes neuronal degeneration and ultimately, leads to memory loss. However, due to the lack of suitable tools, researchers were unable to determine whether mitochondrial alterations played a causal role in these conditions or were simply a consequence of the pathophysiological process.

In this pioneering study, researchers developed a unique tool that temporarily stimulates mitochondrial activity. By activating G proteins directly in mitochondria using an artificial receptor called mitoDreadd-Gs, they successfully restored both mitochondrial activity and memory performance in dementia mouse models.

“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases,” explains Giovanni Marsicano, Inserm research director. “Impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration.”

The tool developed by researchers has opened doors to considering mitochondria as a new therapeutic target for treating memory loss associated with neurodegenerative diseases. Further studies are needed to measure the effects of continuous stimulation of mitochondrial activity and determine its potential impact on symptoms and neuronal loss.

Ultimately, this research holds promise for identifying molecular and cellular mechanisms responsible for dementia, facilitating the development of effective therapeutic targets, and potentially delaying or even preventing memory loss associated with neurodegenerative diseases.

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Alzheimer’s risk may start at the brain’s border, not inside it

The brain’s health depends on more than just its neurons. A complex network of blood vessels and immune cells acts as the brain’s dedicated guardians – controlling what enters, cleaning up waste, and protecting it from threats by forming the blood-brain barrier.

A new study from Gladstone Institutes and UC San Francisco (UCSF) reveals that many genetic risk factors for neurological diseases like Alzheimer’s and stroke exert their effects within these very guardian cells.

“When studying diseases affecting the brain, most research has focused on its resident neurons,” says Gladstone Investigator Andrew C. Yang, PhD, senior author of the new study. “I hope our findings lead to more interest in the cells forming the brain’s borders, which might actually take center stage in diseases like Alzheimer’s.”
The findings, published in Neuron, address a long-standing question about where genetic risk begins and suggest that vulnerabilities in the brain’s defense system may be a key trigger for disease.

For years, large-scale genetic studies have linked dozens of DNA variants to a higher risk of neurological diseases like Alzheimer’s, Parkinson’s, or multiple sclerosis. Yet, a major mystery has persisted: over 90% of these variants lie not in the genes themselves, but in the surrounding DNA that does not contain the code for making proteins, once dismissed as “junk DNA.”

These regions act as complex dimmer switches, turning genes on or off. Until now, scientists haven’t had a full map of which switches control which genes or in which specific brain cells they operate, hindering the path from genetic discovery to new treatments.

A New Technology Finds Answers

The blood-brain barrier is the brain’s frontline defense – a cellular border made up of blood vessel cells, immune cells, and other supporting cells that meticulously controls access to the brain. Yet, these important cells have been difficult to study, even using the field’s most powerful genetic techniques.

To overcome this, the Gladstone team developed MultiVINE-seq, a technology that allows for the simultaneous analysis of multiple genomic and transcriptomic datasets from individual cells.

The new study utilized this technology to investigate the role of immune cells in the brain’s defense system. The researchers found that certain genetic variants associated with Alzheimer’s disease were more prevalent in immune cells than in neurons or other brain cells.

This suggests that the brain’s guardian cells may play a crucial role in the development and progression of Alzheimer’s disease.
The study also identified a potential new target for treating Alzheimer’s disease: PTK2B, a protein that is involved in the regulation of immune cell activity. The researchers found that therapies targeting PTK2B are already being developed for cancer treatment, and could potentially be repurposed for Alzheimer’s disease.

Location, Location, Location

The study’s findings on the brain’s “guardian” cells point to two new opportunities for protecting the brain. Located at the critical interface between the brain and the body, the cells are continually influenced by lifestyle and environmental exposures, which could synergize with genetic predispositions to drive disease.

Their location also makes them a promising target for future therapies, potentially allowing for drugs that can bolster the brain’s defenses from the “outside” without needing to cross the formidable blood-brain barrier. This work brings the brain’s vascular and immune cells into the spotlight, and could inform new, more accessible drug targets and lifestyle interventions to protect the brain from the outside in.

About the Study

The study, “Human brain vascular multi-omics elucidates disease risk associations,” was published in the journal Neuron on July 28, 2025. The work was supported by several funding agencies, including the National Institute of Neurological Disorders and Stroke, Alzheimer’s Association, BrightFocus Foundation, Cure Alzheimer’s Fund, Ludwig Family Foundation, Dolby Family Fund, Bakar Aging Research Institute, National Institute of Mental Health, National Institute of Aging, Leducq Foundation, and Joachim Herz Foundation.

The scientific community has made significant strides in understanding the complex mechanisms behind Alzheimer’s disease. A recent study by researchers at UC San Francisco has shed light on how microglia, immune cells that play a crucial role in maintaining brain health, can break down and remove toxic proteins associated with the disease. This groundbreaking discovery could pave the way for novel therapeutic approaches to combat Alzheimer’s.

In Alzheimer’s, proteins like amyloid beta clump together, forming plaques that damage the brain. However, in some individuals, microglia effectively engulf and digest these proteins before they can cause harm. The resulting few and smaller clumps are associated with milder symptoms. Researchers at UCSF identified a molecular receptor, ADGRG1, which enables microglia to perform this critical function.

Using a mouse model of Alzheimer’s disease, the researchers observed that the loss of ADGRG1 led to a rapid buildup of amyloid plaques, neurodegeneration, and problems with learning and memory. The study also reanalyzed data from a prior human brain expression study, finding that individuals who died of mild Alzheimer’s had microglia with abundant ADGRG1, whereas those with severe Alzheimer’s had very little ADGRG1.

This discovery has significant implications for the development of new therapies. Since ADGRG1 is one of hundreds of G protein-coupled receptors targeted in drug development, it may be feasible to rapidly translate this finding into new treatments. As Dr. Piao noted, “Some people are lucky to have responsible microglia, but this discovery creates an opportunity to develop drugs to make microglia effective against amyloid-beta in everyone.” The potential for breakthrough therapies is exciting news for those affected by Alzheimer’s and their loved ones.