Harvard scientists are studying an immune therapy that could reverse memory loss in Alzheimer's.

In a study in mice, they identified a protein that slows the action of brain immune cells, and blocking it made it possible to eliminate amyloid plaques associated with cognitive decline.

                                                                                       

A proven approach in oncology could open up new possibilities for combating Alzheimer's, according to a recent study by Harvard experts.

The work focuses on an immune system "checkpoint" molecule, which, when deactivated, showed cognitive improvements in mice undergoing experimental testing.

The study's senior author is Vijay Kuchroo, Samuel L. Wasserstrom Professor of Neurology at Harvard Medical School and Brigham and Women's Hospital, who explained the scope of the research. Kuchroo also directs the Gene Lay Institute for Immunology and Inflammation, a uniting entity of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School.

According to Kuchroo, the team managed to eliminate the expression of a molecule called TIM-3. This protein acts as a natural brake on the brain's immune cells, known as microglia, preventing them from attacking the plaques typical of Alzheimer's disease.

By suppressing TIM-3, microglia were freed to act on the plaques, allowing their removal and, correspondingly, the restoration of memory in the mice examined

                                                                                      

Deactivating checkpoint molecules freed microglia to attack plaques in the brain and improved memory in mice, the researcher explained, summarizing one of the most relevant findings.

The work, which was published in Nature, increases the possibility of translating an already effective method against certain types of cancer to the treatment of Alzheimer's, according to specialists.

"Most cases of Alzheimer's disease (AD), between 90% and 95%, are late-onset. The molecule we studied, called TIM-3, was linked through a genome-wide association study to late-onset Alzheimer's and was found to be a genetic risk factor for the disease," Kuchroo stated in The Harvard Gazette.

And he reviewed the existence of a polymorphism in the TIM-3 gene, HAVCR2, in patients with Alzheimer's.

How the Study Was Conducted

When analyzing the study, the specialist said that TIM-3 is an inhibitory molecule that the immune system uses to deactivate immune cells once they are activated: “TIM-3 belongs to a group of inhibitory molecules called checkpoint molecules, which have been used for cancer treatment.”

                                                                                            

Kuchroo elaborated that if the immune system is activated, checkpoint molecules prevent it from getting out of control. “The best example is that every time you get an infection, like the common cold, your lymph nodes swell because millions of T cells are produced to fight the virus. Once the infection clears, checkpoint molecules act to reduce the number of T cells to normal levels.”

“Cancers have exploited these checkpoint molecules for their own survival, and every time a T cell attacks a tumor cell, it induces the expression of checkpoint molecules so that the T cells don't attack them. The T cells become dysfunctional or exhausted, and the tumor survives,” Kuchroo explained.

In this case, she said, the novelty lies in the fact that, in Alzheimer's disease, there is a buildup of plaque in the brain that is not removed by macrophage-like cells called microglia. Microglia show increased expression of the checkpoint molecule TIM-3.

Asked whether microglia are primarily the brain's immune cells, Kuchroo clarified: “Microglia are the brain's immune cells and perform other important functions. During development, synapses are formed, which are the means by which memory is stored. The problem is that even transient experiences generate memories, so it's helpful to eliminate those that aren't used. Therefore, the main function of microglia cells during development is to eliminate synapses that haven't been used frequently enough to sharpen and maintain memory.” 

                                                                                     

“Once you're born and have developed memories, you don't want to lose them, so between 28 and 40 days after birth in mice and a few months or years after birth in humans, there's a developmental mechanism by which microglia stop pruning to preserve the memories they create,” he continued.

“To prevent microglia from pruning, they increase the expression of the control molecule TIM-3, and these microglia cells become homeostatic—that is, they no longer phagocytose,” he said.

Regarding the difference in TIM-3 in an elderly person with Alzheimer's and one without, Kuchroo noted: “There's a polymorphism in the gene, and in Alzheimer's patients with the polymorphism, TIM-3 is highly expressed in microglia, significantly more than in those without the disease.”

"We discovered this molecule in the immune system's T cells, but it's expressed 100 times more, and in some cases 1,000 times more, in microglia when they're activated," the author postulated.

                                                                                             

“So, the same molecule that reduces the T lymphocyte population to its normal size after infection is used by microglia cells to prevent excessive pruning. However, it also has a disadvantage, as it prevents them from attacking the plaques that accumulate in Alzheimer's disease,” he added.

 Regarding the experiments, he commented: “We used laboratory mice that have deleted the HAVCR2 gene, which produces TIM-3. These mice were created to test the role of TIM-3 in autoimmunity and cancer. We genetically deleted the gene, and in these mice, microglia do not express TIM-3 when activated. This improves plaque clearance and modifies their behavior.”

Referring to the measurement of cognitive behavior, he stated: “When they have plaque in their brain, they don't remember as much. They also have less fear. If you put them in an open space, normal mice hide in a corner to avoid becoming prey. But if they have plaque, they stay in the center of the maze and don't hide. By removing the plaques, memory is restored and that response is restored, because an adequate level of fear is important for survival.”

Regarding a possible TIM-3 therapy for Alzheimer's in humans, Kuchroo mentioned: “The therapy would use an anti-TIM-3 antibody or a small molecule that can block the inhibitory function of TIM-3.”

                                                                                          

Furthermore, the author analyzed the potential impact of this strategy: “Since beta amyloid is also found in the endothelium of blood vessels, many antibodies don't reach the brain, but instead attack blood vessels, causing strokes due to vascular damage. This limits the use of anti-amyloid antibodies in AD. Since TIM-3 is selectively expressed, existing anti-TIM-3 antibodies can be repurposed for the treatment of AD.”

Regarding the development time of the work, he stated: “Five years; each experiment lasts between eight and nine months. We are investigating whether human anti-TIM-3 can stop the development of plaques in the brains of mice with Alzheimer's. We have a mouse model into which the human TIM-3 gene has been inserted, which will be very suitable for evaluating various candidate antibodies for the human disease.”