Elsevier

Neurobiology of Aging

Volume 36, Issue 4, April 2015, Pages 1716-1726
Neurobiology of Aging

Regular article
The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation

https://doi.org/10.1016/j.neurobiolaging.2015.01.003Get rights and content

Abstract

A decrease in neurogenesis in the aged brain has been correlated with cognitive decline. The molecular signaling that regulates age-related decline in neurogenesis is still not fully understood. We found that different subtypes of neural stem cells (NSCs) in the hippocampus were differentially impaired by aging. The quiescent NSCs decreased slowly, although the active NSCs exhibited a sharp and dramatic decline from the ages of 6–9 months and became more quiescent at an early stage during the aging process. The activity of the mammalian target of rapamycin (mTOR) signal pathway is compromised in the NSCs of the aged brain. Activating the mTOR signaling pathway increased NSC proliferation and promoted neurogenesis in aged mice. In contrast, inhibiting the mTOR signaling pathway decreased NSCs proliferation. These results indicate that an age-associated decline in neurogenesis is mainly because of the reduction in proliferation of active NSCs, at least partially because of the compromise in the mTOR signaling activity. Stimulating the mTOR signaling revitalizes the NSCs, restores their proliferation, and enhances neurogenesis in the hippocampus of the aged brain.

Introduction

The United States population is aging. According to the United States Census Bureau, 13.3% of the American population was over 65 years old in 2011 (USA QuickFacts from the US Census Bureau). As more of the Baby Boomer generation, born from 1946 to 1964, reaches the age of retirement, this number will only climb higher. An aging population leads to a higher percentage of geriatric-related diseases, particularly those affecting cognitive functions. Adults experiencing impaired cognitive ability suffer from a lower quality of life and may lose the ability to work or perform normal, day-to-day tasks. Thus, it is important to understand the age-associated memory decline, with the hope of finding approaches to delay this process or to improve memory in the aged individuals.

Hippocampal neurogenesis is related to learning and memory, which is greatly affected by the aging process (Ben Abdallah et al., 2010, Lazarov et al., 2010, Rao et al., 2006). Neural stem and/or progenitor cells (NSCs) have been found in the adult mammalian brain (Gage, 1998). These NSCs can continue to generate new neurons throughout the life span. In the adult mammalian brain, new neurons generated by self-renewing NSCs can be found in the hippocampus (Kempermann and Gage, 2000). These new neurons will then integrate into the existing circuitry (Ming and Song, 2011, Zhao et al., 2006). The fates of NSCs are affected by the external stimuli and the internal signaling pathways (Couillard-Despres et al., 2011, Kempermann et al., 1997). Although seizures and physical exercise are known to increase the number of NSCs, aging dramatically decreases the number of NSCs (Fabel and Kempermann, 2008, Kuhn et al., 1996, Lugert et al., 2010, Parent and Murphy, 2008). As mice age, the total number of NSCs declines (Couillard-Despres et al., 2011). However, some reports suggest that the total number of NSCs does not decline, but rather the NSCs experience increased quiescence (Lazarov et al., 2010, Lugert et al., 2010).

Furthermore, different types of NSCs exist in the dentate gyrus of the hippocampus (Lugert et al., 2010, Ming and Song, 2005). NSCs in the adult hippocampus include quiescent neural stem cells (QNPs) and their progeny, active neural stem cells (ANPs) (Abla and Sanai, 2013, Ahn and Joyner, 2005, Ashton et al., 2012, Encinas et al., 2008, Mignone et al., 2004, Song et al., 2012). Morphologically, QNPs are distinguished by their triangular cell body residing in the subgranular zone (SGZ) and a single process, which crosses the granular cell layer and terminates in the molecular layer of the hippocampus (Encinas et al., 2008). ANPs are derived from QNPs through asymmetric division and are characterized by an oval-shaped cell body that runs horizontal to the SGZ and the absence of long processes like QNPs (Gao et al., 2009, Mignone et al., 2004). The QNPs have very low proliferation rate, although ANPs are active in proliferation. Although studies speculate on how the total number of NSCs changes, few studies have examined how these 2 subtypes of NSCs change throughout the aging process and whether different subtypes of NSCs are differentially impaired by aging. It is also not known whether the changes in NSC number or quiescence occur gradually or whether there is an obvious turning point at a certain age. Our study was designed to address these questions and to elucidate the molecular mechanisms beneath these changes. We examined how QNPs and ANPs each responded to aging, how and when the total number of NSCs and proliferation rates changed throughout age, as well as how to restore the NSC proliferation and neurogenesis in the aged brain.

Section snippets

Animal care

Male C57 BL/6 mice (Jackson Laboratories) were group-housed and kept in a 12/12-hour light and/or dark cycle with free access to food and water (ad libitum). The nestin-enhanced-green fluorescent protein (EGFP) transgenic mice (C57/BL6) were kindly provided by Dr Enikolopov at Cold Spring Harbor Laboratories and were described previously (Mignone et al., 2004). The animals were used in experiments at ages of 3, 6, 9, 12, and 18 months. All procedures were performed under protocols approved by

Age-associated reduction of NSCs in the hippocampus is mainly because of the reduction of ANPs

We took advantage of a strain of Nestin-EGFP transgenic mice (Mignone et al., 2004), in which NSCs are easily visualized and different subtypes of NSCs (QNPs and ANPs) are distinguishable to first quantify the total number of NSCs in the hippocampus at different ages up to 18 months. Nestin-EGFP transgenic mice at different ages (3, 6, 9, 12, and 18 months) were sacrificed, and their brains were removed to assess NSCs with an antibody against EGFP. EGFP-positive NSCs are visualized in the SGZ

Discussion

Our study found that the total number of NSCs in the hippocampus decreased dramatically throughout age. Age-related decrements in hippocampal neurogenesis have been suggested as a basis for learning impairment during aging (Bizon et al., 2004, Gage et al., 1989, Lister and Barnes, 2009).

Virtually everyone loses memory making and cognitive abilities as they age. Normal age-associated cognitive decline is obvious after the age of 50 years and picks up speed after that (Hedden and Gabrieli, 2004).

Conclusion

Studies in mice have demonstrated that aging selectively impaired the amplifying neural precursor cells in the hippocampus. The results from this study identified mTOR signaling as a molecular signaling that regulates proliferation of NSCs and that potentially can be targeted to enhance neurogenesis for attenuating cognitive decline in the aging brain. We observed a promising phenomenon that short-term activation of mTOR signaling revitalizes NSCs in the aged mouse. However, a recent study

Disclosure statement

The authors indicate no potential conflicts of interest.

Acknowledgements

This work was supported by funding from the Indiana Spinal Cord & Brain Injury Research Grants (SCBI 200-12), the Ralph W. and Grace M. Showalter Research Award, Indiana University Biological Research Grant, National Institutes of Health (NIH) grants RR025761, 1R21NS075733-01A1, 1R21NS072631-01A1, and the Chinese Program of Introducing Talents of Discipline to Universities (B14036).

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