Human Hippocampal Neurogenesis Persists throughout Aging - PubMed (original) (raw)

. 2018 Apr 5;22(4):589-599.e5.

doi: 10.1016/j.stem.2018.03.015.

Camille A Fulmore 2, Alexandria N Tartt 2, Laika R Simeon 2, Ina Pavlova 3, Verica Poposka 4, Gorazd B Rosoklija 5, Aleksandar Stankov 4, Victoria Arango 6, Andrew J Dwork 7, René Hen 8, J John Mann 6

Affiliations

Human Hippocampal Neurogenesis Persists throughout Aging

Maura Boldrini et al. Cell Stem Cell. 2018.

Abstract

Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

Keywords: Ki-67; NeuN; PSA-NCAM; Sox2; dentate gyrus; doublecortin; granule cells; nestin; neural progenitor; volume.

Copyright © 2018 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Fewer Quiescent Neural Progenitors and Stable Proliferating Intermediate Neural Progenitors in Aging Human Dentate Gyrus

(A and B) Co-expression of sex determining region Y-box 2 (Sox2) and nestin in QNPs; 4’,6-diamidino-2-phenylindole (DAPI) stained nuclei. (C) Sox2+ type I QNPs in the subgranular zone (SGZ) with apical processes crossing the granule cell layer (GCL) into the molecular layer (ML). (D) Sox2+ type II INPs in SGZ. (E) Glial fibrillary acid (GFAP)+ QNPs with apical process (white arrow) and hilar astrocytes and nestin+ INP (yellow arrow). (F) Nestin/Ki-67+ INP. (G and H) Nestin+ INPs (black arrows) and capillaries (red arrows); INP processes touch remodeling capillaries of tubular morphology. (I and J) Nestin/Ki-67+ INPs (yellows arrows) and capillary (green arrow). (K and L) Ki-67+ cells in SGZ/GCL and differential interference contrast image of Ki-67+ nuclei. (M) Sox2+ cell decline in anterior-mid DG with aging. (N and O) Nestin+ and Ki-67+ cells do not decline with older age in anterior, mid, or posterior DG.

Figure 2

Figure 2. Fewer Polysialylated-Neural-Cell-Adhesion-Molecule-Positive Cells in Aging Human Dentate Gyrus

(A) PSA-NCAM+ cells in subgranular zone (SGZ) and granule cell layer (GCL) with processes projecting into the molecular layer (ML). (B and C) PSA-NCAM+ cells of immature, unipolar, and pyramidal morphology. (D–F) Fewer PSA-NCAM+ cells with aging in anterior DG. (G) Immature, unipolar, and pyramidal cell soma volume is stable with aging.

Figure 3

Figure 3. Preserved Immature and Mature Neurons and Glia in Aging Human Dentate Gyrus

(A) Polysialylated neural cell adhesion molecule (PSA-NCAM) and doublecortin (DCX) expression in an immature neuron between subgranular zone (SGZ) and granule cell layer (GCL), two PSA-NCAM+/DCX− cells, and 4’,6-diamidino-2-phenylindole (DAPI)+ nuclei. (B and C) DCX+ cells in SGZ, without and with stained processes. (D) PSA-NCAM/NeuN+ cell with apical dendrite crossing the GCL. (E) NeuN+ neurons in the granule cell layer (GCL), the molecular layer (ML), and subgranular zone (SGZ) are outlined; these outlines were used to calculate DG and GCL-SGZ volumes. (F) NeuN+ neurons and Nissl+ glia in GCL and hilus. (G–I) Stable DCX+ immature neurons, NeuN+ mature granule neurons, and Nissl+ glia.

Figure 4

Figure 4. Age-Associated Dentate Gyrus Angiogenesis Decline and Stable DG Volume

(A) Nestin+ capillaries and neural progenitors and Nissl+ granule cells and glia; the outlined DG region was used to quantify cell numbers and DG volume. (B) Differential interference contrast image of the quadrant in (A); nestin+ progenitors (green arrows) and capillaries (red arrows) are shown. (C) Nestin/Ki-67+ progenitor (green arrow) and Ki-67+ endothelial cell (red arrow) in remodeling capillary; 4’,6-diamidino-2-phenylindole (DAPI) stained nuclei. (D–G) Fewer, shorter, less branched capillaries of smaller areas in anterior-mid DG occur with aging. (H and I) DG and GCL-SGZ volumes are constant with aging.

Comment in

Similar articles

Cited by

References

    1. Aimone JB, Deng W, Gage FH. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron. 2011;70:589–596. - PMC - PubMed
    1. Ben Abdallah NM, Slomianka L, Lipp HP. Reversible effect of X-irradiation on proliferation, neurogenesis, and cell death in the dentate gyrus of adult mice. Hippocampus. 2007;17:1230–1240. - PubMed
    1. Bergmann O, Liebl J, Bernard S, Alkass K, Yeung MS, Steier P, Kutschera W, Johnson L, Landén M, Druid H, et al. The age of olfactory bulb neurons in humans. Neuron. 2012;74:634–639. - PubMed
    1. Bergmann O, Spalding KL, Frisén J. Adult Neurogenesis in Humans. Cold Spring Harb. Perspect. Biol. 2015;7:a018994. - PMC - PubMed
    1. Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, Arango V. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376–2389. - PMC - PubMed

Publication types

MeSH terms

Grants and funding

LinkOut - more resources