Trends in Neurosciences
ReviewWhen neurogenesis encounters aging and disease
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
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