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New Neurons Until Ninety: Discovering Neurogenesis in the Adult Hippocampus

New Neurons Until Ninety: Discovering Neurogenesis in the Adult Hippocampus content piece image
Immature neurons (red) and mature neurons (blue) in the dentate gyrus of a 68-year-old neurologically healthy subject. Credit: Llorens Lab.
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Far from being a capability that ends in maturity, a new study has found that the adult human brain is able to produce new neurons until the tenth decade of life. This ability is substantially impaired in the brains of people with Alzheimer’s Disease (AD), which researchers say could help predict the onset of AD.

The study, led by the Universidad Autónoma de Madrid’s Dr Maria Llorens-Martín, is published in Nature Medicine.

Neurogenesis, the formation of neurons within the brain, begins during embryonic development, and is largely complete by birth. Adult neurogenesis is thought to be limited to certain areas of the brain, and its presence and significance have been hotly contested. In the present study, a region of the hippocampus called the dentate gyrus was examined.

Researchers claimed to have first found evidence of neurogenesis in the hippocampus over 20 years ago, but subsequent studies have had mixed results. Llorens-Martín’s team sought to settle the debate with a large study of samples from 58 different human participants. The donors ranged from 43 to 97 years of age, with both healthy and AD-affected patients studied.

The authors noted that, in general, neurogenesis rates declined with age, but recently matured neurons were still detectable across the adult human lifespan in the 13 non-AD brain samples they assessed.

Proper preparation essential to track down neurogenesis

The findings, as authors noted in the paper, contrasted with a recent study that implied neurogenesis was not present in the adult hippocampus. Llorens-Martín suggested that differences in how the tissue samples were prepared could account for the discrepancy, “Studying the human brain is not easy and often different labs reach different conclusions about a given issue. Long fixation times impede the detection of DCX protein (a marker for neurogenesis) in human tissue.” The markers that tell researchers whether a neuron is immature are detected by histological staining of fixated neural tissues. Llorens-Martín’s study varied the type and duration of fixation and staining used and showed that the number of immature neurons that could be detected varied hugely between different staining methods. They also found that extended chemical treatment reduced detectable neurogenesis to zero. What else might be hiding in brain samples, obscured by the choice of staining procedure used? Moving quickly is essential, says Llorens-Martín, “Post-mortem tissue degradation might be one important factor that could affect the integrity of several proteins. In our experience, post-mortem delays (the time elapsed between exitus and sample immersion in fixative) up to 38 hours are suitable to visualize immature neurons in the human dentate gyrus.”

The hippocampus, a key site of memory and learning function in the brain, is widely understood to be one of the regions most affected by AD, and the presence of immature neurons is important to hippocampus-dependent memory. The authors were therefore keen to see whether brains with Alzheimer’s pathology were also capable of neurogenesis. Across all ages, healthy hippocampuses contained more newly matured neurons than those of AD patients. Nonetheless, neurogenesis was still detectable in AD brains, even in samples from a 97-year old patient. There was also no corresponding reduction seen in mature neuron number, said Llorens-Martín. 

Impaired neurogenesis: a predictor of disease?

Llorens-Martín points out that these deficits in immature neurons number weren’t just seen in AD brains with significant markers of disease, but also in patients with only mild pathology, prior to the deposition of hallmark amyloid plaques and tau tangles. “Our data show an early reduction in the number of DCX+ cells (immature neurons) before the presence of remarkable amounts of beta-amyloid and phosphorylated tau in the dentate gyrus (although the toxic effects of monomers and oligomers of these molecules cannot be completely ruled out),” said Llorens-Martín in an interview. “These data indicate that a reduction in the number of DCX+ neurons in the dentate gyrus is an early event occurring in the course of AD pathology.”

If these impairments in neurogenesis were able to be detected in a non-invasive manner, they might function as an early biomarker of AD, enabling early detection of the disease. Furthermore, said the authors in a press release, “If it were possible to increase the birth and maturation of the new neurons in a similar way to that done in laboratory mice, new therapeutic possibilities could be opened that could be useful to alleviate or slow down the progression of this disease."

Nevertheless, there is still much research to be done – even at the basic level of understanding why some neural populations keep replicating whilst others remain dormant. “We do not know why neurogenesis persists in the adult brain. We know that, in rodents, it is important for certain types of hippocampal-dependent memory and for mood regulation. But we still do not know whether these cells play the same roles in humans,” said Llorens-Martín.