Vesicles secreted by human neural stem cells can protect neurons from damage in Alzheimer’s disease

In a new study published in Stem Cell Research and Therapy, researchers at the Texas A&M University College of Medicine found that tiny packages released by human neural stem cells—called extracellular vesicles—can shield neurons, the brain cells responsible for sending and receiving signals, from damage caused by a toxic protein that is increased in Alzheimer’s disease. These proteins, known as Aβ-42 oligomers (Aβ-42o), are believed to play a central role in causing the loss of synapses—connectivity between neural cells—memory and mood problems, and neural cell death in Alzheimer’s disease.

The study was conducted by the laboratory of Ashok K. Shetty, PhD, University Distinguished Professor in the Department of Cell Biology and Genetics, and associate director of the Institute for Regenerative Medicine at the College of Medicine.

Alzheimer’s disease affects more than 7 million Americans and is projected to cost $384 billion for health and long-term care in 2025. The disease slowly destroys memory and thinking skills and worsens over time, eventually affecting a person’s ability to carry on a conversation or complete simple tasks.

Although the full causes of Alzheimer’s remain unclear, researchers are working to better understand the biological mechanisms driving the disease. One area of focus is Aβ-42o—short stacks of a larger protein, amyloid beta, that can accumulate in the brain and eventually form the amyloid plaques characteristic of Alzheimer’s disease. Even before these plaques develop, Aβ-42o has been shown to damage neurons directly and cause a chain reaction that leads to neuron death.

Extracellular vesicles (EVs) are small nano sacs containing a wide variety of proteins and small pieces of ribonucleic acid (RNA) shed by many kinds of cells known as microRNAs. EVs produced by stem cells are of particular interest to scientists because they contain beneficial proteins and RNA, the secreted products of the parental cell, that can promote cell repair and survival.

An earlier publication from Shetty’s lab showed that these tiny particles secreted by neural stem cells could help considerably reduce brain inflammation mediated by specific brain cells, called microglia and astrocytes, in an animal model of Alzheimer’s disease, which led to the maintenance of better cognitive and mood function. Now, the team has found that these particles also offer direct protection to human neurons.

“This is an exciting discovery because it points out that human neural stem cell-derived EVs can have positive effects on several targets in the Alzheimer’s brain,” Shetty said.

Shama Rao, PhD, a postdoctoral research associate in Shetty’s lab and lead author of this study, explained that these EVs contain potent molecules with antioxidant, anti-inflammatory and neuroprotective properties.

“We wanted to know if they could specifically protect human neurons against the toxic effects of Aβ-42o,” Rao said.

Without any protective treatment, human neurons challenged with this toxic protein start to generate increased amounts of reactive oxygen species, a type of unstable molecule produced due to the overactivation of mitochondria, the powerhouse of cells in our body. Increased reactive oxygen species, if not destroyed, can damage deoxyribonucleic acid (DNA), RNA and proteins, eventually causing cell death through apoptosis, a process that rids the body of damaged cells beyond repair, Rao explained.

In this study, the researchers exposed healthy human neurons to Aβ-42o. These neurons generated increased concentrations of reactive oxygen species, displayed mitochondrial impairments, and increased phosphorylation of tau protein—a hallmark of Alzheimer’s causing neurofibrillary tangles, which are twisted strands of tau protein within neurons—a precursor to neuron death. They also displayed increased expression of genes and proteins that promote cell death and reduced autophagy, a natural process by which cells recycle old and damaged cell parts and proteins to build new cellular organelles and maintain metabolic fitness.

However, when the researchers added isolated EVs generated from neural stem cells generated from human induced pluripotent stem cells, they saw a significant reduction in all harmful effects of Aβ-42o on human neurons.

By examining the specific levels of certain molecular factors, genes and proteins, the research team found that the EVs reduced the buildup of reactive oxygen species, restored mitochondrial function, reduced factors that trigger cell death, and increased autophagy leading to better cell viability and fitness. Notably, the protective effects increased with higher doses of neural stem cell EVs.

These findings demonstrate the potential of using neural stem cell-derived EVs as a therapy for not only protecting neurons from damage but even reversing damage caused by Aβ-42o that leads to progressively increasing cognitive decline in Alzheimer’s disease.

“These results are very promising, but additional research is needed to verify what other pathways through which EVs could be counteracting Aβ-42o, particularly their impact on the electrical functioning and the possible expression of multiple protective genes in human neurons exposed to Aβ-42o,” Shetty said.