Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer's Disease Patients - PubMed (original) (raw)

Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer's Disease Patients

Matthew K Tobin et al. Cell Stem Cell. 2019.

Abstract

Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin+Sox2+ neural progenitor cells (NPCs) and DCX+ neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin+ cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX+PCNA+ cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX+PCNA+ cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.

Keywords: Alzheimer’s disease; adult neurogenesis; aging; cognitive dysfunction; human neurogenesis; neural stem cells; neurogenesis in aging.

Copyright © 2019 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of Interests: The authors declare no competing financial interests.

Figures

Figure 1.

Figure 1.. Counts of neural progenitor cells in the hippocampus of aged humans.

a-c. Cell counts in the SGL: Nestin+ (a), PCNA+ (b), Nestin+PCNA+ (c). d-f. Cell counts in the GCL: Nestin+ (d), PCNA+ (e), and Nestin+PCNA+ (f). g-i. Cell counts upweighted to DG volume: Nestin+ (g), PCNA+ (h), and Nestin+PCNA+ (i). j-l. Total cell counts in the DG: Nestin+Sox2+ (j), Nestin+Ki67+ (k), Nestin+Sox2+Ki67+ (l). m-o Cell counts upweighted to DG volume. Nestin+ (m), Nestin+Ki67+ (n), Nestin+Sox2+Ki67+ (o). Data represent the mean ± SEM of all 18 subject with each data point corresponding to a single subject. Clinical diagnosis is color coded (black = normal, no cognitive impairments, blue = mild cognitive impairments, red = Alzheimer’s disease). p,q. Representative images of Nestin+Sox2+ (p) or Nestin+Sox2+Ki67+ (q) -expressing cells. (GCL and SGL are noted, white outline = area presented in high power on the right). Scale bar represents low magnifications images (left panel): 20 μm, high magnification images (right panel): 10 μm.

Figure 2.

Figure 2.. Quantification of neuroblasts and immature neurons in the hippocampus of aged humans.

a-c. Number of DCX+ cells in the SGL (a), GCL (b) and whole DG (c). d-f. Number of DCX+PCNA+ cells in the SGL (d), GCL (e) and whole DG (f). Data represent the mean ± SEM of all 18 subject with each data point corresponding to a single subject. Clinical diagnosis is color coded (black = normal, no cognitive impairments, blue = mild cognitive impairments, red = Alzheimer’s disease). g. Representative images of DCX - expressing cells co-stained with DAPI (GCL and SGL are noted, white outline = area presented in high power on the right). Scale bar Top and Middle Panels: low magnification 20 μm, high magnification 20 μm. Bottom Panel: low magnification 10 μm, high magnification 20 μm.

Figure 3.

Figure 3.. Correlation of cell numbers along the dorsal/ventral axis of the hippocampus.

a-c. Correlation of Nestin+ (a), PCNA+ (b), and DCX+ (c) cell counts in the SGL. d-f. Correlation of Nestin+ (d), PCNA+ (e), and DCX+ (f) cell counts in the GCL. g-n. Correlation of total Nestin+ (g), PCNA+ (h), DCX+ (i), Nestin+Sox2+ (j), Nestin+PCNA+ (k), Nestin+Ki67+ (l), Nestin+Sox2+Ki67+ (m) and DCX+PCNA+ (n) cell counts upweighted to DG volume. Coefficients (β) were estimated with each cell volume normalized with mean and standard deviation.

Figure 4.

Figure 4.. Association of neurogenesis with cognitive diagnosis and presynaptic proteins.

a,b. Logistic regression analysis of cognitive diagnosis and the number of DCX+PCNA+ cells shows significant correlation with MCI (p=0.038) (a) and borderline significance with MCI+AD (p=0.067) (b). c,d. Association between the number of DCX+PCNA+ (c) or Nestin+Sox2+Ki67+ (d) cells and global cognition score (p=0.046, p=0.098, respectively). e. Association between the number of DCX+PCNA+ cells and SNARE protein-protein interaction (p=0.0038). f. Representative image showing the distribution of presynaptic proteins in the dentate gyrus of the hippocampus inner molecular layer (IML), granule cell layer (GCL), subgranular layer (SGCL) and CA4 subfield. SNAP-25 immunostaining (magenta) with cell nuclei stained with DAPI (green) in a section of brain where DCX+PCNA+ cells were identified. Scale bar representes 25 μm.

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