Murine Features of Neurogenesis in the Human Hippocampus across the Lifespan from 0 to 100 Years

By R. Knoth, I. Singeç, M. Ditter, G. Pantazis, P. Capetian, R. P. Meyer, Volker Horvat, B. Volk, Gerd Kempermann. 2010

661 citations recorded by the source corpus.

Background Essentially all knowledge about adult hippocampal neurogenesis in humans still comes from one seminal study by Eriksson et al. in 1998, although several others have provided suggestive findings. But only little information has been available in how far the situation in animal models would reflect the conditions in the adult and aging human brain. We therefore here mapped numerous features associated with adult neurogenesis in rodents in samples from human hippocampus across the entire lifespan. Such data would not offer proof of adult neurogenesis in humans, because it is based on the assumption that humans and rodents share marker expression patterns in adult neurogenesis. Nevertheless, together the data provide valuable information at least about the presence of markers, for which a link to adult neurogenesis might more reasonably be assumed than for others, in the adult human brain and their change with increasing age. Methods and Findings In rodents, doublecortin (DCX) is transiently expressed during adult neurogenesis and within the neurogenic niche of the dentate gyrus can serve as a valuable marker. We validated DCX as marker of granule cell development in fetal human tissue and used DCX expression as seed to examine the dentate gyrus for additional neurogenesis-associated features across the lifespan. We studied 54 individuals and detected DCX expression between birth and 100 years of age. Caveats for post-mortem analyses of human tissues apply but all samples were free of signs of ischemia and activated caspase-3. Fourteen markers related to adult hippocampal neurogenesis in rodents were assessed in DCX-positive cells. Total numbers of DCX expressing cells declined exponentially with increasing age, and co-expression of DCX with the other markers decreased. This argued against a non-specific re-appearance of immature markers in specimen from old brains. Early postnatally all 14 markers were co-expressed in DCX-positive cells. Until 30 to 40 years of age, for example, an overlap of DCX with Ki67, Mcm2, Sox2, Nestin, Prox1, PSA-NCAM, Calretinin, NeuN, and others was detected, and some key markers (Nestin, Sox2, Prox1) remained co-expressed into oldest age. Conclusions Our data suggest that in the adult human hippocampus neurogenesis-associated features that have been identified in rodents show patterns, as well as qualitative and quantitative age-related changes, that are similar to the course of adult hippocampal neurogenesis in rodents. Consequently, although further validation as well as the application of independent methodology (e.g. electron microscopy and cell culture work) is desirable, our data will help to devise the framework for specific research on cellular plasticity in the aging human hippocampus.

Subfields: Developmental Neuroscience, Psychiatry and Mental health, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Human Hippocampal Neurogenesis Persists throughout Aging (2018, positive): “The density of doublecortin-positive (DCX+) cells were reported to decline from birth into the tenth decade of life (Knoth et al., 2010) in parallel with 14C-determined neuron turnover (Bergmann et al., 2015); however, medication and drug use, which affect AHN (Boldrini et al., 2014), were not…”
Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults (2018, neutral): “In humans, some studies suggest that hundreds of new neurons are added to the adult DG every day 11 , while other studies find many fewer putative new neurons 12–14 .”
Evidence for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers (2017, background): “The two available studies of neurogenesis in the aging human hippocampus using immunohistochemical (Knoth et al., 2010) and carbon dating (Spalding et al., 2013) techniques suggest that hippocampal neurogenesis is progressively reduced with age but employed markers that were either relatively…”
The role of adult hippocampal neurogenesis in brain health and disease (2018, methodology): “2 to 59 years revealed that proliferating cells in the SGZ rapidly decline in early childhood [88], consistent with an earlier study [7].”
Human adult neurogenesis: evidence and remaining questions (2018, positive): “Several earlier studies have used DCX to assess adult neurogenesis in humans (Dennis et al., 2016; Galán et al., 2017; Knoth et al., 2010; Liu et al., 2008; Mathews et al., 2017).”
Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later (2015, background): “Most studies have relied upon histological analysis using postmortem samples, but we are limited to a few markers, such as NESTIN and DCX (Knoth et al., 2010).”
Neurodegenerative disease and adult neurogenesis (2011, background): “…(DCX) as a marker of neurogenesis in the adult human hippocampus; however, the morphology of these cells is somewhat different from rodent brains (Knoth et al., 2010) and it remains questionable how well preserved the stained cells in human brains are and how they reflect the generation of new…”
Adult Neurogenesis in Humans. (2015, methodology): “In humans, doublecortin (DCX) and polysialylated neuronal cell adhesion molecule (PSA-NCAM)-expressing putative neuroblasts are found in both the dentate gyrus (DG) of the hippocampus (Knoth et al. 2010) in the lateral ventricle wall (Sanai et al.”
Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. (2014, background): “As judged by expression of polySia and other markers, the pattern of dentate gyrus neurogenesis in humans (238) is comparable to the situation in rodents (435, 444) and undergoes similar qualitative and quantitative age-related changes.”
Neurogenesis in the striatum of the adult human brain. (2014, positive): “Themorphology of the DCX-positive cells in the striatum varied from rounded without processes, elongated with few processes to highly branched (Figures 1C–1F), similar to the neuroblasts in the subventricular zone and hippocampus (Knoth et al., 2010; Sanai et al., 2011; Wang et al., 2011).”