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Comparative Study
. 2006 Dec 13;26(50):13114-9.
doi: 10.1523/JNEUROSCI.4667-06.2006.

Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain

Jadranka Macas  1 , Christian Nern, Karl H Plate, Stefan Momma
Affiliations
Comparative Study

Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain

Jadranka Macas et al. J Neurosci. .

Abstract

The adult human brain retains the capacity to generate new neurons in the hippocampal formation (Eriksson et al., 1998) and neuronal progenitor cells (NPCs) in the forebrain (Bernier et al., 2000), but to what extent it is capable of reacting to injuries, such as ischemia, is not known. We analyzed postmortem tissue from normal and pathological human brain tissue (n = 54) to study the cellular response to ischemic injury in the forebrain. We observed that cells expressing the NPC marker polysialylated neural adhesion cell molecule (PSA-NCAM) are continuously generated in the adult human subventricular zone (SVZ) and migrate along the olfactory tracts. These cells were not organized in migrating chains as in the adult rodent rostral migratory stream, and their number was lower in the olfactory tracts of brains from old (56-81 years of age) compared with young (29 + 36 years of age) individuals. Moreover, we show that in brains of patients of advanced age (60-87 years of age), ischemia led to an elevated number of Ki-67-positive cells in the ipsilateral SVZ without concomitant apoptotic cell death. Additionally, ischemia led to an increased number of PSA-NCAM-positive NPCs close to the lateral ventricular walls, compared with brains of comparable age without obvious neuropathologic changes. These results suggest that the adult human brain retains a capacity to respond to ischemic injuries and that this capacity is maintained even in old age.

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Figures

Figure 1.
Figure 1.
Cellular architecture and proliferative capacity of the adult human SVZ. a, Schematic overview of a human brain hemisphere with the dotted red line indicating the area of analysis. b, c, Representative histology of the SVZ with a gap between the ependymal layer and astrocytic ribbon in the medial part (b) and with the astrocytic ribbon being continuous from the ependymal layer to the brain parenchyma in the dorsal and ventral areas (c). d, Occasionally, PSA-NCAM-positive cells can be detected close to the ependyma or in the astrocytic ribbon and beyond. e, f, Molecules that were shown to regulate neurogenesis such as notch1 (e) and Flk-1/VEGFR-2 (f) are expressed in the ependymal cell layer. g, Proliferating Ki-67-positive cells are often closely associated with the ependymal layer. h, i, Lack of costaining with pan-hematopoietic markers such as CD45 (h) rules out a non-neural origin of the proliferating Ki-67-positive cells (i). Scale bars: b, c, 50 μm; d, g, h, 10 μm; e, f, 25 μm; i, 20 μm.
Figure 2.
Figure 2.
Decrease in the production of NPCs migrating along the olfactory tract with age. a, b, Olfactory tracts of younger individuals (a) show a much higher number of PSA-NCAM-positive cells than those of old patients (b). c, PSA-NCAM-positive cells have an elongated morphology (b, d, inset) and costain with the marker TuJ1. e, Merged image with TOTO-3 iodide-labeled nuclei. Scale bars: a, b, 25 μm; c, 10 μm.
Figure 3.
Figure 3.
Increase in cell proliferation and production of PSA-NCAM-positive NPCs in ischemic injuries. a, Schematic drawing of a human brain from a patient that died 5 d postischemia with a large area of necrotic tissue in the right hemisphere (area shaded in gray). The areas that were analyzed by immunohistochemistry are delineated by red dotted lines. b, For quantitation, the subventricular area was divided into two zones: zone I was defined as the area from the ependymal layer to the adjacent brain parenchyma including the astrocytic ribbon (white dotted line); zone II encompasses the tissue from the astrocytic ribbon to deeper layers of the brain parenchyma. c, d, In the ipsilateral side to the injury, the number of proliferating cells close to the lateral ventricular walls increased (d) compared with the contralateral side (c). Ki-67-positive cells are indicated with arrowheads. e, f, Likewise, the production of PSA-NCAM-positive NPCs is lower in contralateral (e) compared with the ipsilateral side (f). g, h, Proliferation (g) and the number of PSA-NCAM-positive NPCs (h) is much higher in the ventricular zone of the late-developing compared with the adult human brain. i, PSA-NCAM-positive cells can be detected only rarely at the penumbra of the stroke area (area indicated by red dotted rectangle in a). j, k, Quantitation of Ki-67- (j) and PSA-NCAM-positive (k) cells per millimeter squared in zone I and II; ipsilateral and contralateral sides were compared with each other for both zones and each ischemic case with every control. Error bars indicate ±SD. Statistical significance was calculated by Student's unpaired t test; j, *p < 0.005, **p < 0.0005; k, *p < 0.05, **p < 0.005. Controls were not significantly different from each other, assessed by one-way ANOVA. Scale bars: b, 100 μm; c, d, 20 μm; e, f, h, i, 50 μm.
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