The LT-Neuroscience︱Debate on birth of new neurons in AD

Copy Writing (English)︱Ashley Yeager, The Scientist 

Layout Editing︱LTNeurosci, The LT-Neuroscience

Photo: Professor María Llorens-Martín’s lab.

Despite doubts last year about human adult neurogenesis, a study shows even 80-year-olds develop new cells in the hippocampus, but such growth is diminished in patients with Alzheimer’s disease (AD).

New neurons develop in the brains of healthy adult humans, but neurogenesis is severely diminished in the brains of AD patients no matter their age, researchers report today (March 26) in Nature Medicine.

“This is the first really strong evidence showing that neurogenesis is reduced in human Alzheimer’s disease patients,” Xinyu Zhao, a neurobiologist at the University of Wisconsin-Madison who was not involved in the study, tells The Scientist. Perhaps, the authors suggest, finding a way to promote neurogenesis in these patients could help in treating AD.

The paper is the latest to tackle the question of whether neurogenesis actually occurs in adult human brains. A year ago, researchers reported that they couldn’t find signs of new neuron growth in brain tissue samples taken from people who had died or patients who had epilepsy. About a month later, however, a separate team reported they had found evidence of abundant neurogenesis in a different set of samples. 

Fig. 1 Adult hippocampal neurogenesis is a robust phenomenon in the dentate gyrus of neurologically healthy adult human subjects.

In the latest study, María Llorens-Martín, a neuroscientist at the Autonomous University of Madrid, and her colleagues analyzed postmortem brain tissue of 13 healthy individuals that were between 43 and 87 years old and of 45 patients with AD between 52 and 97 years old. 

“The most important factor is fixation of the samples,” Llorens-Martín tells The Scientist. In the study, she and her colleagues tested whether the time of fixation—how long the samples sat in a preservation chemical—affected the detection of new neurons, which is typically measured by the presence of a protein called doublecortin (DCX). The results showed that two to 12 hours was the optimal time for the samples to sit in the chemical, while sitting longer than 24 hours nearly wiped out the DCX signal.

Fig. 2 differentiation stages of adult hippocampal neurogenesis in the dentate gyrus of neurologically healthy adult human subjects.

The tissue preparation methodology is similar to what researchers used last year to find evidence of new neuron growth in adult humans, Zhao says. But it’s a bit different from the methods used in the study that didn’t find neurogenesis, which froze samples and let some of them sit in the preservation chemical for longer than 24 hours. Using very strict protocols to preserve and process the brain tissue samples, Llorens-Martín and her colleagues identified thousands of immature neurons in the dentate gyrus—a part of the hippocampus related to memory-making—in neurologically healthy humans, even when they are in their eighties. “It is another strong piece of evidence that indeed there is adult neurogenesis in older people,” Zhao says.

The results show that neurogenesis does decrease moderately with age. But the number of immature neurons in healthy people appears to be consistently higher than the number found in patients with AD regardless of their age. These patients typically had tens of thousands fewer immature neurons compared with healthy subjects and the loss of cells progressed with the severity of the disease, the team found.

Not everyone is convinced by the results. In an email to The Scientist, Shawn Sorrells, a neuroscientist at the University of Pittsburgh and a coauthor of last year’s study finding no evidence of adult human neurogenesis, writes, “accurately identifying newborn neurons is a complicated endeavor requiring multiple lines of evidence to rule out alternative explanations, none of which are presented in this study.” The cells’ appearance and protein profiles, he notes, suggest they are “actually a distinct set of mature hippocampal neurons that have been there since childhood.”

Fig. 3 Adult hippocampal neurogenesis is impaired in patients with AD.

Zhao disagrees and says the new study is actually the first to provide a clear view of the maturation of newly developing neurons in the human adult brain. In rodent models, scientists have shown that in addition to DCX, developing neurons produce a calcium-binding protein called CR when they are less mature and one called CB when they are a little farther along in their development. In the new study, Llorens-Martín and her colleagues used a labeling technique to identify the cells expressing both DCX and CR and those expressing both DCX and CB and then tracked where they existed in a part of the hippocampus called the subgranular zone. The cells expressing DCX and CR were located at the border of this part of the hippocampus and had smaller cell bodies and were more elongated, characteristic of less mature cells. Cells labeled for DCX and CB were located deeper in the dentate gyrus and had more of an oval shape, indicating they were more mature.

Tracing the cells this way is important to show for certain that they are maturing into new neurons, Maura Boldrini, a neurobiologist at Columbia University who was not involved in the new study, tells The Scientist. A criticism of past experiments has been that the neurons may be transforming into some other types of cells, but the new work clearly shows the immature cells are becoming actual neurons. Boldrini was a coauthor of the 2018 study providing evidence of neurogenesis in adult humans.

Fig. 4 Maturation of dCX ⁺ cells is impaired in the dentate gyrus of patients with AD. 

Boldrini also explains the result showing that such cells are diminished in AD patients independent of their age is important because it reinforces the idea—demonstrated in animal models—that the disease is a condition caused by some pathology other than aging. Sorrells agrees that the finding is worthy of more study, though he suggests the cells, which he and his colleagues propose are a distinct subpopulation of hippocampus neurons present since childhood, are possibly more susceptible to the disease. “This in and of itself,” he says, “would be an important phenomenon to understand.”

Llorens-Martín notes that the loss in those cells appears early in the brains of patients with AD, even before the development of the amyloid plaques and neurofibrillary tangles characteristic of the disease. Therefore, the loss of these particular cells might become a biomarker for the early development of the disease. And, she says, if researchers can show in humans that neurogenesis can improve memory—as they’ve shown in animal models—then spurring new neurons to grow in the hippocampi of Alzheimer’s patients could lead to novel therapeutics to treat the disease.

E.P. Moreno-Jiménez et al., “Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease,” Nature Medicine, doi:10.1038/s41591-019-0375-9, 2019

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