Date Published: August 01, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Kathryn J. Mathews, Katherine M. Allen, Danny Boerrigter, Helen Ball, Cynthia Shannon Weickert, Kay L. Double.
Reduced neurogenesis in the aging mammalian hippocampus has been linked to cognitive deficits and increased risk of dementia. We utilized postmortem human hippocampal tissue from 26 subjects aged 18–88 years to investigate changes in expression of six genes representing different stages of neurogenesis across the healthy adult lifespan. Progressive and significant decreases in mRNA levels of the proliferation marker Ki67 (MKI67) and the immature neuronal marker doublecortin (DCX) were found in the healthy human hippocampus over the lifespan. In contrast, expression of genes for the stem cell marker glial fibrillary acidic protein delta and the neuronal progenitor marker eomesodermin was unchanged with age. These data are consistent with a persistence of the hippocampal stem cell population with age. Age‐associated expression of the proliferation and immature neuron markers MKI67 and DCX, respectively, was unrelated, suggesting that neurogenesis‐associated processes are independently altered at these points in the development from stem cell to neuron. These data are the first to demonstrate normal age‐related decreases at specific stages of adult human hippocampal neurogenesis.
Neurogenesis persists in the subgranular zone of the adult human hippocampus and arises from a pool of quiescent stem cells which, if appropriately stimulated, undergo proliferation and subsequent maturation into neurons. These new neurons are thought to play an important role in normal hippocampal function, particularly in the ongoing maintenance of hippocampus‐dependent spatial and declarative memory (Aimone et al., 2014; Christian et al., 2014). It has therefore been hypothesized that alterations in hippocampal neurogenesis may be a contributing factor to cognitive decline and dementia. This is supported by observations that radiation‐induced ablation of hippocampal neurogenesis in rats results in cognitive decline (Monje et al., 2002) and clinical evidence of cognitive changes in patients receiving radiation therapy and chemotherapy (Monje & Dietrich, 2012). Further evidence of a relationship between hippocampal neurogenesis and cognitive function is provided by disorders associated with cognitive decline, including Alzheimer’s disease (Boekhoorn et al., 2006) and Parkinson’s disease (Hoglinger et al., 2004) where stem cell proliferation and/or nascent neuron maturation is altered.
KM contributed to the conception and design of this study, experimental procedures, statistical analysis and writing of the manuscript. KA and DB contributed to the experimental procedures and editing of the manuscript. HB contributed to the statistical analysis and editing of the manuscript. CSW contributed to the conception and design of this study and editing of the manuscript. KD contributed to the conception and design of this study, statistical analysis and editing of the manuscript.
This study was supported by the Discipline of Biomedical Science at the University of Sydney, the Schizophrenia Research Institute (utilizing infrastructure funding from the NSW Ministry of Health and the Macquarie Group Foundation), the University of New South Wales and Neuroscience Research Australia. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). Tissues were received from the New South Wales Brain Tissue Resource Centre at the University of Sydney supported by the Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism (NIAAA).
No conflicts of interest have been reported by any of the authors involved in the publication of this study.