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Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years.

Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, Horvat V, Volk B, Kempermann G - PLoS ONE (2010)

Bottom Line: Total numbers of DCX expressing cells declined exponentially with increasing age, and co-expression of DCX with the other markers decreased.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropathology, University of Freiburg, Freiburg, Germany.

ABSTRACT

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.

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A, B Proliferation markers Ki67 or PCNA, co-expressed with the developmental and lineage markers DCX and Prox1, identified SGZ cells as cycling neuronal precursor cells.C–E, The SGZ of juvenile and adult subjects exhibits immature DCX+ cells co-expressing development markers characteristic also for developing adult-generated granule cells in rodents. C, In neonates, some immature granule cells co-express DCX and early postmitotic neuronal marker, TUC4. Glia (arrow) did not react against the neuron-specific antibodies applied. D, Early neuro-ectodermal marker nestin labels a bipolar DCX+ cell and neuropil structures not matching GFAP+ astrocytic processes in the PML of a 6 years-old subject. E, Transcription factor Sox2, characteristic for precursor cells, remains expressed in DCX+ cells lacking the transitional maturation marker calretinin. F–H, Lineage markers were co-stained with DCX up to oldest age. F, β-III-tubulin, the early neuronal cytoskeleton marker, is expressed also in a DCX+/Prox1+ cell of a 100 year-old individual. G, At age 38 years, NeuroD1, one of the earliest known lineage markers in precursor cells, was detected in a round-shaped DCX+ precursor weakly reactive for maturation marker NeuN (asterisk). H, Even at age 100 years, granule cell-specific transcription factor Prox1 and transient postmitotic neuronal maturation marker calretinin were found together with DCX. I–L, Immunoreactivity for neuronal maturation markers in DCX+ cells between 2 month and 75 years. I, Bipolar migratory DCX+ cell expressed markers of neuronal transmission, like glutamatergic and GABAergic receptors (GluR4 and GABAARec.) K, DCX+/Prox1+ cells may show GABAergic synapses, here demonstrated by GAD65 in axonal terminals around the cell soma. L, MAP2ab immunostaining could be found among matured DCX+ cells in the adult SGZ. Length of scale bars as indicated.
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pone-0008809-g007: A, B Proliferation markers Ki67 or PCNA, co-expressed with the developmental and lineage markers DCX and Prox1, identified SGZ cells as cycling neuronal precursor cells.C–E, The SGZ of juvenile and adult subjects exhibits immature DCX+ cells co-expressing development markers characteristic also for developing adult-generated granule cells in rodents. C, In neonates, some immature granule cells co-express DCX and early postmitotic neuronal marker, TUC4. Glia (arrow) did not react against the neuron-specific antibodies applied. D, Early neuro-ectodermal marker nestin labels a bipolar DCX+ cell and neuropil structures not matching GFAP+ astrocytic processes in the PML of a 6 years-old subject. E, Transcription factor Sox2, characteristic for precursor cells, remains expressed in DCX+ cells lacking the transitional maturation marker calretinin. F–H, Lineage markers were co-stained with DCX up to oldest age. F, β-III-tubulin, the early neuronal cytoskeleton marker, is expressed also in a DCX+/Prox1+ cell of a 100 year-old individual. G, At age 38 years, NeuroD1, one of the earliest known lineage markers in precursor cells, was detected in a round-shaped DCX+ precursor weakly reactive for maturation marker NeuN (asterisk). H, Even at age 100 years, granule cell-specific transcription factor Prox1 and transient postmitotic neuronal maturation marker calretinin were found together with DCX. I–L, Immunoreactivity for neuronal maturation markers in DCX+ cells between 2 month and 75 years. I, Bipolar migratory DCX+ cell expressed markers of neuronal transmission, like glutamatergic and GABAergic receptors (GluR4 and GABAARec.) K, DCX+/Prox1+ cells may show GABAergic synapses, here demonstrated by GAD65 in axonal terminals around the cell soma. L, MAP2ab immunostaining could be found among matured DCX+ cells in the adult SGZ. Length of scale bars as indicated.

Mentions: We next established whether DCX expression in the human DG could be linked to other markers that in the rodent are associated with adult hippocampal neurogenesis (Complete list in Table S4). The findings are summarized in Fig. 6, examples are shown in Figs. 7 and 8.


Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years.

Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, Horvat V, Volk B, Kempermann G - PLoS ONE (2010)

A, B Proliferation markers Ki67 or PCNA, co-expressed with the developmental and lineage markers DCX and Prox1, identified SGZ cells as cycling neuronal precursor cells.C–E, The SGZ of juvenile and adult subjects exhibits immature DCX+ cells co-expressing development markers characteristic also for developing adult-generated granule cells in rodents. C, In neonates, some immature granule cells co-express DCX and early postmitotic neuronal marker, TUC4. Glia (arrow) did not react against the neuron-specific antibodies applied. D, Early neuro-ectodermal marker nestin labels a bipolar DCX+ cell and neuropil structures not matching GFAP+ astrocytic processes in the PML of a 6 years-old subject. E, Transcription factor Sox2, characteristic for precursor cells, remains expressed in DCX+ cells lacking the transitional maturation marker calretinin. F–H, Lineage markers were co-stained with DCX up to oldest age. F, β-III-tubulin, the early neuronal cytoskeleton marker, is expressed also in a DCX+/Prox1+ cell of a 100 year-old individual. G, At age 38 years, NeuroD1, one of the earliest known lineage markers in precursor cells, was detected in a round-shaped DCX+ precursor weakly reactive for maturation marker NeuN (asterisk). H, Even at age 100 years, granule cell-specific transcription factor Prox1 and transient postmitotic neuronal maturation marker calretinin were found together with DCX. I–L, Immunoreactivity for neuronal maturation markers in DCX+ cells between 2 month and 75 years. I, Bipolar migratory DCX+ cell expressed markers of neuronal transmission, like glutamatergic and GABAergic receptors (GluR4 and GABAARec.) K, DCX+/Prox1+ cells may show GABAergic synapses, here demonstrated by GAD65 in axonal terminals around the cell soma. L, MAP2ab immunostaining could be found among matured DCX+ cells in the adult SGZ. Length of scale bars as indicated.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2813284&req=5

pone-0008809-g007: A, B Proliferation markers Ki67 or PCNA, co-expressed with the developmental and lineage markers DCX and Prox1, identified SGZ cells as cycling neuronal precursor cells.C–E, The SGZ of juvenile and adult subjects exhibits immature DCX+ cells co-expressing development markers characteristic also for developing adult-generated granule cells in rodents. C, In neonates, some immature granule cells co-express DCX and early postmitotic neuronal marker, TUC4. Glia (arrow) did not react against the neuron-specific antibodies applied. D, Early neuro-ectodermal marker nestin labels a bipolar DCX+ cell and neuropil structures not matching GFAP+ astrocytic processes in the PML of a 6 years-old subject. E, Transcription factor Sox2, characteristic for precursor cells, remains expressed in DCX+ cells lacking the transitional maturation marker calretinin. F–H, Lineage markers were co-stained with DCX up to oldest age. F, β-III-tubulin, the early neuronal cytoskeleton marker, is expressed also in a DCX+/Prox1+ cell of a 100 year-old individual. G, At age 38 years, NeuroD1, one of the earliest known lineage markers in precursor cells, was detected in a round-shaped DCX+ precursor weakly reactive for maturation marker NeuN (asterisk). H, Even at age 100 years, granule cell-specific transcription factor Prox1 and transient postmitotic neuronal maturation marker calretinin were found together with DCX. I–L, Immunoreactivity for neuronal maturation markers in DCX+ cells between 2 month and 75 years. I, Bipolar migratory DCX+ cell expressed markers of neuronal transmission, like glutamatergic and GABAergic receptors (GluR4 and GABAARec.) K, DCX+/Prox1+ cells may show GABAergic synapses, here demonstrated by GAD65 in axonal terminals around the cell soma. L, MAP2ab immunostaining could be found among matured DCX+ cells in the adult SGZ. Length of scale bars as indicated.
Mentions: We next established whether DCX expression in the human DG could be linked to other markers that in the rodent are associated with adult hippocampal neurogenesis (Complete list in Table S4). The findings are summarized in Fig. 6, examples are shown in Figs. 7 and 8.

Bottom Line: Total numbers of DCX expressing cells declined exponentially with increasing age, and co-expression of DCX with the other markers decreased.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropathology, University of Freiburg, Freiburg, Germany.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus