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1Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Campus Cantoblanco, 28049 Madrid, Spain.
2Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
Received date: June 08, 2011; Accepted date: July 15, 2011; Published date: July 17, 2011
Citation: Avila J (2011) A Possible Role for GSK3 in the Impaired Neurogenesis and Memory Loss Associated with Alzheimer´s Disease and Aging. J Alzheimers Dis Res 1:102e. doi:10.4172/2161-0460.1000102e
Copyright: © 2011 Avila J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder that in a minority of cases (familial AD), is due to a specific mutation in one of the following three genes: app, ps-1 and ps-2, [1]. However, in the majority of cases (sporadic AD), the origin of the disease remains unknown, although several risk factors have been identified that may facilitate disease onset, among which aging is the prime factor. In tissues with a high cell turnover, functional impairment (aging) may be related to a decrease in the tissue's regenerative potential, probably reflecting a reduction in the capacity of resident stem cells to maintain the tissue's structure [2]. However, the central nervous system is a structure with very little cell turnover and in adult mammals, neurogenesis mainly takes place in only two regions of the brain: the subventricular zone and the subgranular zone of the dentate gyrus (DG) [3]. Nevertheless, the new neurons generated in the DG integrate with the pre existing neurons, and they are thought to play an important role in learning and memory [4]. Thus, reduced DG neurogenesis may account for the impaired learning and memory associated with AD. The role of aging and the depletion of dentate gyrus stem cells (or neuronal precursors) in the memory loss observed in both the elderly and in AD patients has been addressed in different studies. Indeed, evidence suggests that a loss of neuronal precursors may underlie the decline in neurogenesis [5] and the loss of cognitive functions [6] associated with aging. The reduction observed in the number of neuronal precursors which accompanies aging is mediated by multiple factors, including decreases in levels of the SIRT-1 deacetylase. SIRT-1 was recently shown to promote Wnt signaling [7], which may in turn decrease GSK3 activity. Thus, it can be postulated that deregulation of GSK3 activity occurs with aging, although it remains unclear whether such effects may occur in nervous tissue. In familiar AD, mutations in the app, ps-1 or ps-2 genes promote disease onset [8], and while this may be dependent [9,10] or independent [11-13] of increases in beta amyloid peptide, GSK3 activation augments in both scenarios. Increased GSK3 activity is believed to participate in sporadic AD [14], in conjunction with different apolipoprotein E variants, and GSK3ß has also been implicated in this disease [15]. Accordingly, reduced Wnt/ß- catenin signaling in response to GSK3 activation has been described in the brains of AD patients [16]. A loss of ß-catenin expression has also been described in these patients [17], while interruption of ß-catenin signaling through elevating GSK3 levels reduces neurogenesis in AD [18]. These observations suggest a link between neurogenesis in the dentate gyrus, GSK3 and Alzheimer’s disease. As such, a mouse model overexpressing GSK3 in the dentate gyrus was developed [19] in an attempt to reproduce some of the characteristics of AD patients. Indeed, like patients this mouse model exhibited a significant memory impairment [20] and subsequent studies linked this impairment with age-dependent degeneration of the dentate gyrus [21]. Furthermore, aberrant neurogenesis was observed in the subgranular zone of the dentate gyrus in this model [22], similar to that described in a transgenic mouse over expressing mutated presenilin-1 [23]. Aberrant neurogenesis in the dentate gyrus has been described in the brain of AD patients and it may affect the morphogenesis of newborn neurons [24]. A clear degeneration of the dentate gyrus has not been described in AD patients, although failed connections between the dentate gyrus and the entorhinal cortex via the perforant path have been described [25]. In addition, hippocampal atrophy has been visualized in AD patients through in vivo imaging techniques [26,27] and hippocampal sclerosis is associated with advanced age in humans [28]. Thus, it is feasible that AD might somehow accelerate some aging-related processes, including the decrease in the formation of new functional neurons. A prolonged suppression of neurogenesis will provoke a wide range of compensatory changes in the structure and dynamics of the dentate gyrus in young but not in old mice [29]. At present it remains unclear whether a similar process may occur in early and late onset forms of AD, which could explain some of the differences in the degree of hippocampal atrophy observed in both these forms of the disease. In summary, on the basis of a large amount of data it can be hypothesized that impaired neurogenesis in the dentate gyrus promotes the loss of memory observed in AD patients. This impaired neurogenesis may be the result of the depletion and/or aging of neuronal precursors in the dentate gyrus. Indeed, transplantation of neuronal stem cells in the dentate gyrus has been proposed as a means to replace damaged precursor cells or to promote the formation of new neurons [30]. While some positive results were obtained with this approach in a mouse of neuronal loss, new complementary ideas approaches should be developed to maintain neurogenesis in the dentate gyrus of the elderly and/or of AD patients.
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