C.harlie Arber, stem cell biologist at University College London, works with induced pluripotent stem cell models of inherited forms of dementia. When he and his colleagues began studying several cell lines from patients with familial forms of Alzheimer’s disease a few years ago, the first thing they noticed was that the cells developed into neurons faster than stem cells from healthy individuals. he says.
The researchers took a closer look at the Alzheimer’s cell lines and published them in a study published Jan. 12 Cell reports, confirmed that neurogenesis – the production of neurons from precursors – occurs much earlier in these lineages. When they looked up in the brains of familial Alzheimer’s patients after death, they found fewer newborn neurons than in the brains of healthy donors, suggesting that the premature neurogenesis observed in stem cell lines is likely a feature of familial Alzheimer’s disease that leads to outbreaks of newborns leads to neurons in early adulthood, followed by defects in neurogenesis as people age.
Long before this study, scientists suggested that adult neurogenesis and Alzheimer’s disease were linked. In 1998, Salk Institute neuroscientist Rusty Gage and colleagues examined the human brain postmortem and found evidence of neurogenesis in adults in the hippocampus, the brain center associated with learning, memory, and emotional responses – some of the cognitive tasks that are impaired in Alzheimer’s disease. The birth of neurons had previously been shown in rodents and non-human primates, but not in humans.
Since then, work on animal models and humans has shown that neurogenesis of the hippocampus plays an important role in memory formation in adults and that the decrease in neurogenesis is associated with aging, as well as the cognitive loss and development of Alzheimer’s disease, of which 10 percent of Americans older than 65. But scientists are still finding out at what point in the onset or progression of the disease hippocampal neurogenesis plays a role in adults and whether optimizing neurogenesis is used to treat or prevent it Illness may or may not contribute.
Neural stem cells in the granular cell layer (GCL) and subgranular layer (SGL) of the dentate gyrus of the hippocampus are indicated by arrows. Cell nuclei are blue.
Researchers have made advances in looking directly at neurogenesis in humans, but their efforts are not without challenges.
As a PhD student, María Llorens-Martín, now a neuroscientist at the Autonomous University of Madrid, showed that increasing neurogenesis in adults had neuroprotective effects on cognitively impaired mice. Then about 10 years ago as a postdoc she started collecting human brain samples to study adult neurogenesis in humans. However, she quickly realized that the samples available in most brain banks are not suitable for studying neurogenesis in adults because of their processing and preservation.
When the researchers compared healthy subjects with patients with cognitive impairment, particularly those with Alzheimer’s disease, the reduction in the number of new neurons was dramatic.
When a brain is donated to a brain bank, the standard procedure is usually to soak the tissue in a fixative for several weeks, which allows researchers to later cut and image thin sections of tissue. However, this lengthy process repairs tell-tale markers on newborn neurons so the antibodies the researchers use to detect them don’t work on the samples, explains Llorens-Martín.
When the researchers instead fixed the brain for 24 hours, they were able to detect evidence of neurogenesis in the hippocampus. In a study published in 2019, Llorens-Martín and her colleagues confirmed previous work showing that neurogenesis in adults gradually declines with age, even in healthy people. And when the researchers compared healthy subjects with patients with cognitive impairment, particularly those with Alzheimer’s disease, the reduction in the number of new neurons was dramatic. “Even in very young subjects who were diagnosed with Alzheimer’s, the number of new neurons was very much reduced compared to neurologically healthy older subjects,” she says.
In another 2019 study, a group led by Orly Lazarov, a neuroscientist at the University of Illinois at Chicago, looked at the postmortem hippocampi of 18 people between the ages of 79 and 99. They found evidence of neurogenesis in all subjects, including those diagnosed with mild cognitive impairment or Alzheimer’s disease. The number of neural progenitors and newborn neurons was linked to cognitive status: people with higher numbers of these cells generally had higher cognitive scores and a less severe diagnosis.
“There is growing evidence that neurogenesis of the hippocampus plays an important role in the cognitive decline of Alzheimer’s disease in adults,” says Lazarov. Her work and that of others have shown that neurogenesis is compromised early in Alzheimer’s disease (AD). In mouse models, for example, her group noticed differences in neurogenesis as early as two and three months of age – the equivalent of a person by the age of 20. They and others have also found that further depletion of neurogenesis exacerbates cognitive defects in AD rodent models. It is possible that “impairments in neurogenesis are not just a side effect of AD pathology,” she says, but “part of the mechanism by which memory is impaired in disease.”
In their latest work, Arber and colleagues show that neurogenesis in induced pluripotent stem cells looks similar to that in the human brain, which means that stem cell models could help answer the question of cause or effect. And when defects in neurogenesis actually drive neurodegeneration, a new path of intervention opens up.
All cells in an organoid of the human brain are marked in blue and newborn neurons are marked in red.
Charles Arber, Selina Wray and Christopher Lovejoy
“We diagnose people when they are seventy or seventy-five years old. It’s too late to intervene, ”says Caghan Kizil, neuroscientist at the German Center for Neurodegenerative Diseases. “But we do know that molecular or pathological onset starts much earlier,” he adds, which means that scientists and doctors could potentially block the process by potentially optimizing neurogenesis.
In a study published in January 2020, Kizil and colleagues identified two distinct populations of neural stem cells that respond to signaling pathways that regulate neurogenesis in a zebrafish model of Alzheimer’s disease. They found a role for brain-derived neurotrophic factor (BDNF), a protein that, when elevated, is also involved in cognitive improvements in a mouse model of Alzheimer’s disease. BDNF supports the survival, maturation and maintenance of neurons in healthy brains. In the study, Rudolph Tanzi, neuroscientist at Harvard University, Gage, and colleagues improved cognition in the animals by stimulating neurogenesis, either genetically or with drugs, and artificially increasing BDNF levels in the hippocampus. The results indicate that manipulating neurogenesis and optimizing neuron survival could be a potential treatment for Alzheimer’s disease.
Even if researchers develop therapeutics that block or reduce the progression of the disease, they won’t reverse the damage, says Nicolas Toni, a neuroscientist at Lausanne University Hospital in Switzerland and a former postdoc at the Gage laboratory. “Neural death has occurred as soon as the patient realizes that he or she has memory problems and those neurons are lost,” he says, but adult neurogenesis in the hippocampus could be a way to partially correct this injustice. “The most important question is whether we can manipulate neurogenesis in adults. And is that enough to relieve some of the symptoms of Alzheimer’s disease? ”
Developing drugs to increase neurogenesis and an inexpensive live imaging strategy or diagnostic test that can directly link neurogenesis and cognition in humans will be important steps, but well into the future, says Gage. “At least in rodents, where increased neurogenesis has positive effects, there is little evidence that increasing your neurogenesis could injure you, but there is always some [safety] as a concern, ”he adds.
The most difficult question to answer, according to Llorens-Martín, is what happens to the few new neurons that are born in the brain of people with neurodegeneration. “What is failing in the environment that is causing these neurons to die prematurely or making it very difficult for them to connect properly?” She says. “It is known that systemic changes in the blood occur, for example in Alzheimer’s patients several decades before the onset of cognitive impairment,” she says. It’s possible that these changes in the systemic environment, or that of the brain, somehow decrease the neurogenic potential of the hippocampus, she adds.
“We know that neurogenesis is critical to learning and memory, and we know that the level of neurogenesis decreases with age, no matter what, even with normal aging,” says Lazarov. “And if we say so [a] higher level of neurogenesis. . . We would be able to maintain greater hippocampal plasticity and intact hippocampal function. This can significantly delay Alzheimer’s disease. “