Trends in Neurosciences
Volume 33, Issue 12, December 2010, Pages 569-579
Journal home page for Trends in Neurosciences

Review
When neurogenesis encounters aging and disease

https://doi.org/10.1016/j.tins.2010.09.003Get rights and content

In this review, we consider the evidence that a reduction in neurogenesis underlies aging-related cognitive deficits and impairments in disorders such as Alzheimer's disease (AD). The molecular and cellular alterations associated with impaired neurogenesis in the aging brain are discussed. Dysfunction of presenilin-1, misprocessing of amyloid precursor protein and toxic effects of hyperphosphorylated tau and β-amyloid probably contribute to impaired neurogenesis in AD. Because factors such as exercise, environmental enrichment and dietary energy restriction enhance neurogenesis, and protect against age-related cognitive decline and AD, knowledge of the underlying neurogenic signaling pathways could lead to novel therapeutic strategies for preserving brain function. In addition, manipulation of endogenous neural stem cells and stem cell transplantation, as stand-alone or adjunct treatments, seems promising.

Introduction

There is a progressive decline in the regenerative capacity of most organs with increasing age, resulting in functional deterioration and poor repair from injury and disease. Once thought to exist only in high-turnover tissues, such as the intestinal lining or bone marrow, it now appears that most tissues harbor stem cells that contribute to tissue integrity throughout life. In many cases, stem cell numbers decrease with age, suggesting that stem cell aging could be of fundamental importance to the biology of aging ([1] for review). Therefore, understanding the regulation of stem cell maintenance and/or activation is of considerable relevance to understanding the age-related decline in the maintenance of tissue integrity, function, and regenerative response.

The adult brain contains neural stem cells (NSCs) that self-renew, proliferate and give rise to neural progenitor cells (NPC) that exhibit partial lineage-commitment. Following several cycles of proliferation, NPC differentiate into new neurons and glia. NSCs are increasingly acknowledged to be of functional significance and harbor potential for repair of the diseased or injured brain. The dramatic decline in neurogenesis with age may contribute to impairments in learning and memory. Aging is also the greatest risk factor for Alzheimer's disease (AD), a neurodegenerative disease characterized by progressive loss of memory and cognitive decline. Alterations in neurogenesis have been described extensively in animal models of AD, and key proteins involved in AD pathogenesis have been shown to regulate neurogenesis. By understanding the molecular mechanisms underlying neurogenesis and its decline with aging it could become possible to manipulate NSCs to treat for brain disorders.

Section snippets

Neurogenesis in the adult mammalian brain

There are two neurogenic areas in the adult brain: the subventricular zone (SVZ) abutting the lateral ventricles, which contains NSCs that give rise to neurons in the olfactory bulb, and the subgranular layer (SGL) in the dentate gyrus (DG) of the hippocampus, in which NSCs become new granule cell neurons (Figure 1). Thus, the adult brain has more capacity for plasticity at the cellular level than was previously thought. The prevailing hypothesis holds that the putative NSCs of the SVZ are

Neurogenesis and learning and memory

Newly formed neurons are thought to play a role in brain function. In particular, the role of neurogenesis in olfaction and in hippocampal-dependent learning and memory seems to be multifaceted. Several approaches have been taken to elucidate the role of hippocampal neurogenesis in learning and memory (Box 1 for a summary of the methods used). It is crucial for the interpretation of the data obtained in these studies to consider the method of intervention (chemical, genetic, environmental), the

Neurogenesis and aging

Both germinal centers, the SVZ and the SGL, exhibit an age-related decline in the production of new neurons [31]. The age-related decline in cell proliferation and new neurons in the SVZ has been linked to functional decline in olfaction in mice [32], and in the SGL is associated with decline in hippocampal-dependent spatial memory 31, 33, 34. Despite an age-related reduction in the formation of new hippocampal neurons, the neurons that are added appear functionally equivalent to those in young

Neurogenesis impairments in AD

Progressive memory loss and cognitive decline are the fundamental characteristics of AD. In addition, individuals afflicted with the disease experience difficulties in learning, speed of performance, recall accuracy and problem solving (see Ref. [44] for review). Impaired olfactory function (deficits in olfactory sensitivity, odor discrimination, and odor identification) appears to be one of the earliest detectable functional alterations in AD, and olfactory sensitivity and olfactory

Physiological roles of APP and PS1 in neurogenesis

Although several studies have shown that transgenic mice expressing mutant APP or PS1 show impaired adult neurogenesis, little is known of the physiological role of either protein in neurogenesis. For example, APP is processed into three main fragments and all three proteolytic products have been shown to modulate neurogenesis differently. A soluble fragment of APP generated by α-secretase (sAPPα), exerts proliferative effects on embryonic NSC and also stimulates proliferation of progenitor

Modulation of neurogenesis by the environment in aging and in AD

Hippocampal neurogenesis can be regulated by environmental factors. In particular, environmental enrichment has been shown to be a positive regulator of adult neurogenesis [15]. Subsequent research revealed that the main neurogenic component of the enriched environment is physical activity (see Refs. 68, 69 and Figure 2). Exercise-induced neurogenesis is correlated with improved learning and memory 16, 68, possibly by modulation of bone morphogenetic protein (BMP) signaling 70, 117.

Modulation of neurogenesis as a therapeutic approach: minding the neurogenic niche

The studies described above imply that modulation of self-renewal, proliferation, migration and differentiation of endogenous NPCs could hold great promise for the maintenance of brain plasticity, the preservation of learning and memory capabilities, the prevention of aging-linked decline in neurogenesis, and for the repair of the diseased brain. A prerequisite for the modulation of neurogenesis is the identification of molecular targets regulating these processes. The neurogenic niche is

Stem cell therapy for the aging brain

Given the age-related increase in burden of neurological diseases and injury, such as stroke, the idea of transplanting NPCs into the impaired aging brain has great appeal. As discussed above, despite the reduction in neurogenesis in the aged brain and the delayed maturation of the newly generated neurons, the aged hippocampus appears to retain sufficient environmental niche signals to support the normal maturation of new neurons. Indeed, there are a few reports describing cognitive improvement

Conclusion and future directions

The existence of neurogenic niches in the adult mammalian brain has initiated much hope for the use of NSCs for the therapy of the aging and diseased brain. Enhancement of brain plasticity, learning and memory, improved cognition and attenuation of neurodegeneration are only some of the high expectations of this therapy. Whether exogenous neural stem and/or progenitor cells are transplanted or endogenous cells are locally recruited, their successful survival, differentiation, and functional

Acknowledgements

The authors’ work was supported by the National Institutes of Health grants AG033570, AG036208Z (O.L.), AG20047 and AG22555 (D.A.P.) and AG026146 (S.W.P.); the Intramural Research Program of the National Institute on Aging (M.M. and H.v.P.); Alzheimer's Association Young Investigator Award, Alzheimer's disease Research Fund, the Illinois Department of Public Health, and the Brain Research Foundation (O.L.). The authors thank Archana Gadadhar, Yuan-shih Hu and Michael Demars for producing images

References (119)

  • O. Lazarov et al.

    Neurogenesis and Alzheimer's disease: at the crossroads

    Exp. Neurol.

    (2010)
  • C. Zhang

    Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease

    Exp. Neurol.

    (2007)
  • Q. Chen

    Adult neurogenesis is functionally associated with AD-like neurodegeneration

    Neurobiol. Dis.

    (2008)
  • G. Li

    GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice

    Cell Stem Cell

    (2009)
  • B. Sun

    Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal model of Alzheimer's disease

    Cell Stem Cell

    (2009)
  • H. Yu

    APP processing and synaptic plasticity in presenilin-1 conditional knockout mice

    Neuron

    (2001)
  • P.H. Wen

    The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice

    Exp. Neurol.

    (2004)
  • S.H. Choi

    Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation

    Neuron

    (2008)
  • P.H. Wen

    Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice

    Neurobiol. Dis.

    (2002)
  • R. Wang

    Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis

    Neuroscience

    (2004)
  • N.L. Chevallier

    Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation

    Am. J. Pathol.

    (2005)
  • G. Kronenberg

    Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus

    Neurobiol. Aging

    (2006)
  • S. Lugert

    Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging

    Cell Stem Cell

    (2010)
  • S.A. Wolf

    Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer's disease

    Biol. Psychiatry

    (2006)
  • K. Nichol

    Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice

    Alzheimers Dement.

    (2009)
  • J. Ninkovic et al.

    Signaling in adult neurogenesis: from stem cell niche to neuronal networks

    Curr. Opin. Neurobiol.

    (2007)
  • F. Doetsch

    A niche for adult neural stem cells

    Curr. Opin. Genet. Dev.

    (2003)
  • F. Doetsch

    Subventricular zone astrocytes are neural stem cells in the adult mammalian brain

    Cell

    (1999)
  • R. Seidenfaden

    Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain

    Mol. Cell Neurosci.

    (2006)
  • D.A. Lim

    The adult neural stem cell niche: lessons for future neural cell replacement strategies

    Neurosurg. Clin. N. Am.

    (2007)
  • M. Pathania

    A symphony of signals conducts early and late stages of adult neurogenesis

    Neuropharmacology

    (2010)
  • T. Kobilo

    Neurogenesis and exercise

  • N.E. Sharpless et al.

    How stem cells age and why this makes us grow old

    Nat. Rev. Mol. Cell Biol.

    (2007)
  • H. Suh

    Signaling in adult neurogenesis

    Annu. Rev. Cell Dev. Biol.

    (2009)
  • L. Petreanu et al.

    Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction

    J. Neurosci.

    (2002)
  • A. Carleton

    Becoming a new neuron in the adult olfactory bulb

    Nat. Neurosci.

    (2003)
  • J.C. Platel

    GABA and glutamate signaling: homeostatic control of adult forebrain neurogenesis

    J. Mol. Histol.

    (2007)
  • S. Fukuda

    Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus

    J. Neurosci.

    (2003)
  • A.D. Garcia

    GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain

    Nat. Neurosci.

    (2004)
  • C. Zhao

    Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus

    J. Neurosci.

    (2006)
  • C. Schmidt-Hieber

    Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus

    Nature

    (2004)
  • N. Kee

    Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus

    Nat. Neurosci.

    (2007)
  • K. Shimazu

    NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis

    Learn. Mem.

    (2006)
  • G. Kempermann

    More hippocampal neurons in adult mice living in an enriched environment

    Nature

    (1997)
  • H. van Praag

    Running enhances neurogenesis, learning, and long-term potentiation in mice

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • G. Kempermann et al.

    Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task

    Eur J. Neurosci.

    (2002)
  • V. Lemaire

    Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • J. Raber

    Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis

    Radiat. Res.

    (2004)
  • T.J. Shors

    Neurogenesis may relate to some but not all types of hippocampal-dependent learning

    Hippocampus

    (2002)
  • W. Deng

    New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

    Nat. Rev. Neurosci.

    (2010)
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