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

Abstract

BackgroundEssentially 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 FindingsIn 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.ConclusionsOur 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.

The brain tumor microenvironment

“…It is well established that primary glioblastoma are diagnosed mainly in older patients and are virtually unknown in infants (Ohgaki and Kleihues, 2007). However, adult neurogenesis in primates and humans (as in rodents) also declines massively with aging and may be at a very low level after puberty (Gould et al, 1999;Knoth et al, 2010). This creates the somewhat paradoxical situation that a stem cellrelated disease like glioblastoma [originating from mutant brain stem cells (Sanai et al, 2005)], occurs at a time when there are only very few stem cells left in the brain.…”

Review paper Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?

“…Since neurogenesis is required for memory and learning, and its activity has shown to be decreased after ischemia in humans and rodents [25,26], it has been suggested that impaired hippocampal neurogenesis might be an integral part of postischemic progression [58]. Particularly, a variety of key factors involved in brain ischemia, among them presenilin 1 and 2, amyloid precursor protein and its products β-amyloid peptides, play either a positive or a negative role in hippocampal neurogenesis [7,27].…”

Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies

“…Doublecortin-deficient neurons also show defects in the kinesin-3-motor protein-mediated transport of presynaptic vesicles (2). Anti-doublecortin antibodies are widely used as markers in the immunohistochemical detection of neurogenesis (3) and are therefore important research tools for neuroscience. Recently, basal doublecortin levels were also reported outside of neurogenic regions in the brain (4).…”