Although these protective microglia appear in relatively small numbers, the study showed that they have a powerful influence across the brain. Their presence helps calm harmful inflammation, supports cognitive abilities, and improves survival in mice. In contrast, when the team removed CD28 from this rare group of microglia, inflammation rose sharply and plaques associated with Alzheimer's developed more quickly. This outcome demonstrated how essential CD28 is for enabling the helpful actions of these cells.

Microglia as Flexible and Protective Brain Cells

"Microglia are not simply destructive responders in Alzheimer's disease -- they can become the brain's protectors," explained Anne Schaefer, the senior author of the research and leader of the project. She noted that the findings build on earlier work showing that microglia can adopt a wide range of functional states, allowing them to play many different roles in brain health. According to Schaefer, the results also highlight how international scientific partnerships are crucial for making progress in complex fields like neurodegeneration.

Alexander Tarakhovsky added that it was striking to see immune-related molecules, long recognized for their roles in B and T lymphocytes, also influencing microglia. "This discovery comes at a time when regulatory T cells have achieved major recognition as master regulators of immunity, highlighting a shared logic of immune regulation across cell types," he said. He also pointed out that understanding this shared system may open the door to new immunotherapeutic approaches for Alzheimer's disease.

Genetic Clues That Connect PU.1 to Alzheimer's Risk

The work expands on earlier genetic studies by senior co-author Alison Goate, who identified a common variant in SPI1 (the gene responsible for producing PU.1) that is associated with a lower risk of developing Alzheimer's. Goate explained, "These results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer's risk," offering a clearer picture of how genetics influence disease vulnerability.

Overall, the discovery of the PU.1-CD28 axis provides researchers with a new molecular framework for understanding how protective microglial states arise. It also emphasizes the promise of developing treatments that specifically target microglia in order to alter the course of Alzheimer's disease.

RELATED STORIES

Roughly 20 million adults in the country are living with some form of AMD. People with this condition typically lose the ability to see objects directly in front of them, although their peripheral vision remains intact. Available therapies can slow how the disease progresses, but none of them can restore lost vision.

Exploring a New Cell-Based Approach

In a study published in Cell Stem Cell, scientists tested retinal pigment epithelial stem cells in a phase 1/2a clinical trial. The cells were obtained from adult postmortem eye tissue. These early-stage trials are designed to determine whether a treatment can be safely administered.

AMD occurs in two forms: dry and wet. More than 90% of patients have the dry type, which develops when retinal pigment epithelial cells begin to malfunction and eventually die.

In the early stages of AMD, these cells no longer work correctly. At more advanced stages, they die and cannot regenerate. As the condition worsens, multiple regions in the central retina lose these essential cells.

Transplanting Specialized Stem Cells

In the current study, individuals with advanced dry AMD received transplants of specialized stem cells originally sourced from eye-bank tissue. These adult stem cells were limited in function and could only mature into retinal pigment epithelial cells.

Six participants were given the lowest dose of the treatment (50,000 cells) during an eye surgery. The procedure proved safe, with no serious inflammation or tumor growth reported in any of the patients.

Early Signs of Vision Improvement

Participants also showed vision improvements in the treated eye, while their untreated eye did not show the same changes. This difference suggests that the technique itself may hold therapeutic potential. "Although we were pleased with the safety data, the exciting part was that their vision was also improving," said Rajesh C. Rao, M.D., Leonard G. Miller Professor of Ophthalmology & Visual Sciences, and an associate professor of pathology and human genetics. "We were surprised by the magnitude of vision gain in the most severely affected patients who received the adult stem cell-derived RPE transplants. This level of vision gain has not been seen in this group of patients with advanced dry AMD."

When tested on a standard eye chart, the low-dose group was able to read 21 additional letters one year after treatment.

Next Steps in the Clinical Trial

The research team is now monitoring 12 more participants who received higher doses of 150,000 and 250,000 cells. If no safety issues are identified, the investigators plan to move on to later stages of the clinical trial.

"We are grateful to all our participants who are allowing to better understand whether this intervention is safe enough to be a future therapy," Rao said. "These kinds of NIH-funded studies can help us offer advanced treatments in the field of regenerative medicine, and we are happy we can offer this first-in-human, cutting-edge clinical trial at the University of Michigan."

About Age-Related Macular Degeneration

Age-related macular degeneration is a condition that gradually damages the macula, the small but vital area at the back of the eye that supports sharp central vision. The disease typically develops as people get older, and it is more common in individuals over 60.

There are two primary forms of AMD. The dry form appears most often and involves the slow breakdown of retinal cells that help the eye process detail and color. The wet form is less common but progresses more quickly and involves abnormal blood vessel growth under the retina.

Over time, both types can cause blind spots in central vision, making activities such as reading and identifying faces increasingly difficult. While current treatments can slow the disease, scientists have been searching for ways to restore the lost cells, which is why stem cell research has become a promising direction.

Previous research has already established that smoking raises the likelihood of cardiovascular disease, but the connection between smoking intensity and specific health consequences has been harder to clarify, particularly for light smokers. As more individuals smoke fewer cigarettes than in past decades, understanding both the risks tied to low-intensity smoking and the long-term benefits of quitting has become increasingly important, even for people who do not consider themselves heavy smokers.

Large Multi-Study Review Reveals Long-Term Damage

Blaha's group examined information from more than 300,000 adults who participated in 22 longitudinal studies (which follow individuals over extended periods) for as long as 19.9 years. During that time, more than 125,000 deaths and 54,000 cardiovascular events were recorded, including heart attacks, strokes and heart failure. The results showed that smoking only two to five cigarettes per day was linked to a 50 percent higher risk of heart failure and a 60 percent higher risk of death from any cause compared with people who had never smoked. The greatest reduction in cardiovascular risk occurred within the first 10 years after quitting and continued to improve the longer a person remained smoke-free. Even so, former smokers still had higher risk levels than lifelong non-smokers for as long as three decades after they quit.

Quitting Completely Offers the Strongest Protection

Because even occasional or low-level smoking can sharply increase the chance of heart disease and premature death, the researchers emphasize that stopping entirely at a younger age is the most effective way to reduce long-term harm. Simply cutting back on the number of cigarettes smoked each day does not provide the same protective benefits. These findings support long-standing public health recommendations that encourage early and complete cessation and highlight the need for robust smoking prevention efforts.

Researchers Stress the Impact of Early Cessation

The authors add, "This is one of the largest studies of cigarette smoking to date using the highest quality data in the cardiovascular epidemiology literature. It is remarkable how harmful smoking is -- even low doses of smoking confer large cardiovascular risks. As far as behavior change, it is imperative to quit smoking as early in life as possible, as the among of time passed since complete cessation from cigarettes is more important prolonged exposure to a lower quantity of cigarettes each day."