- Email: [email protected]
Environmental enrichment and neurodegenerative diseases
BBRC Biochemical and Biophysical Research Communications 334 (2005) 293–297 www.elsevier.com/locate/ybbrc
Breakthroughs and Views
Environmental enrichment and neurodegenerative diseases Lingzhi Li, Bor Luen Tang * Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore Received 17 May 2005 Available online 9 June 2005
Abstract Recent reports on experimental models of neurodegeneration in mice have strengthened the notion that environmental enrichment (EE) is beneficial, in terms of delayed onset and progression, to a variety of neurodegenerative diseases. These studies also revealed interesting mechanistic understandings as to how EE might function. While it is generally assumed that EE elicits transcriptional and translational events that on the whole tend to be neuroprotective and neurogenic, fairly specific changes that appear to target the underlying pathological causes of disease in these various mouse models have been noted. These include a possible restoration of brain-derived neurotrophic factor striatal transport in the R6/1 HuntingtonÕs mice and an elevation in the levels of amyloid-degrading enzyme neprilysin in the APPswe/PS1DE9 Alzheimic mice. An elevation in glial-derived neurotrophic factor coupled to a reduction in dopamine transporter may underlie beneficial effects in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced Parkinsonian symptoms. How all these findings would translate to disease settings in human patients are unclear, but they do provide useful leads for further clinical and paraclinical investigations. Ó 2005 Elsevier Inc. All rights reserved. Keywords: AlzheimerÕs disease; Environmental enrichment; HuntingtonÕs disease; ParkinsonÕs disease
Maintenance of a socially and intellectually active lifestyle helps the elderly in maintaining their mental health. This notion is supported by numerous longitudinal data on the association of lifestyles with dementia (reviewed in [1]). This general idea also has good support from experimental animal models of human neurodegeneration, aging, and brain injury [2–4]. In a broad sense, environmental enrichment (EE) is an experimental paradigm in animals which supposedly parallel physical, social, and intellectual activity of humans. These include encouragements to perform physical exercise (e.g., running wheels) and exposure to a variety of passive visual stimuli (e.g., changing colored backgrounds and objects). EE may be beneficial to postnatal neuronal functions and survival in two general ways. First, EE is clearly neurogenic. Gage and co-workers [5,6] have extensively documented that mice exposed to an enriched environ*
Corresponding author. Fax: +65 67791453. E-mail address: [email protected] (B.L. Tang).
0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2005.05.162
ment have significantly more hippocampal neurons compared with those in standard housing, and that EE induces cell proliferation and neurogenesis at the dentate gyrus [7,8]. Second, EE elicits neuroprotective responses, largely in the form of elevation of neurotrophic factors in areas of the brain [9,10]. Furthermore, EE may induce synaptic structural changes that enhance learning and memory [5,11]. A number of recent reports with more elaborate mechanistic investigations have revealed, in each case, some cellular and molecular changes associated with EE that are more model specific. We summarize these observations in the following paragraphs, and ponder on how these may aid clinical and paraclinical investigations in human patients. Environmental enrichment and HuntingtonÕs disease HuntingtonÕs disease (HD) is an autosomal dominant inherited disease belonging to the general group of
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L. Li, B.L. Tang / Biochemical and Biophysical Research Communications 334 (2005) 293–297
inherited neurodegenerative disorders characterized by an expansion of polyglutamine tracts, which in the case of HD is found in the protein hungtingtin [12]. Several transgenic mice models have been developed that recapitulate the progressive cognitive and motor symptoms of HD. Earlier studies have shown that subjecting the popular HD models, the R6/1 mice expressing exon 1 of huntingtin with an expanded number of glutamine repeats, to an enriched environment from four weeks significantly delayed the onset of disease symptoms and degenerative loss of cerebral volume without apparently reducing the formation of striatal neuronal inclusions typical of HD [13]. These beneficial effects are also observed with the R6/2 line with fast disease onset [14]. How exactly does EE act in a way that is beneficial to the HD mice? Human HD brain suffers from a lost of neurotransmitter receptors. Particularly severe loss occurs with the cannabinoid CB1 receptors, which are selectively lost from the basal ganglia output nuclei even prior to onset of disease symptoms [15]. This loss is apparently delayed in mice exposed to EE [16]. One neurotrophic factor that is consistently associated with HD is BDNF. Earlier reports suggest that huntingtin promotes BDNF transcription, and mutant huntingtin loses this function [17]. A recent finding further implicated huntingtin in mediating another aspect of BDNF functionality—its axonal transport. Huntingtin apparently enhances vesicle transport of BDNF along microtubule [18], and BDNF transport is impaired with a loss of functional huntingtin. BDNF is not synthesized at the striatum but are rather transported into it from the anterior cortex via axonal projections [19]. EE has been shown to elevate BDNF levels rather specifically in the striatum of deer mice [20]. In the R6/1 HD model, there is severe reduction of BDNF levels at the striatum, but not the anterior cortex. EE exposure reversed this reduction in striatal BDNF [21]. This suggests that the effect of EE in this case may be to alleviate the block in BDNF transport to the striatum. This block in BDNF transport is specific as nerve growth factor (NGF) levels were unaffected in the striatum in these animals. EE may also delay the deficits of certain key proteins in the HD model. One such protein whose level is reduced by about a quarter in both the striatum and anterior cortex of HD mice is the 32 kDa cAMP-regulated phosphoprotein (DARPP-32), a key regulator of dopamine and serotonin signaling. Interestingly, EE exposure does little to striatal DARPP-32 levels but elevates it in HD mice. The benefit of EE on HD disease onset and progression may therefore involve both transcriptional and post-transcriptional mechanisms.
Environmental enrichment and AlzheimerÕs disease AlzheimerÕs disease (AD) is the most prominent cause of age-related dementia. As mentioned above, a good
number of epidemiological studies have inferred a correlation between AD and intellectual, educational, and social background [1]. The pathophysiology of idiopathic AD is complex, but may in many cases involve neuronal stress and death cause by both soluble and aggregated forms of amyloid-beta (Ab) derived from amyloidegenic processing of the amyloid precursor protein (APP). It was shown using organotypic hippocampal slices prepared from an APP mutant (APPswe) transgenic mice that Ab production is apparently modulated by neuronal activity [22]. Although the experimental setting is fairly in vitro, it provided the first indication that there may indeed be a discernible mechanism that could possibly explain the beneficial effects of cognitively intense activities. It is therefore a little surprising when it was reported that APPswe/PS1DE9 (double-transgenic for mutant APP and presenilin 1, a key component of c-secretase) mice exposed to a short term (several months) enriched environment instead showed an increase in aggregated and total Ab compared to controls in standard caging [23]. In another study, long term EE seems to result in global, overall improvement in cognitive functions, but without decreasing Ab deposition [24]. A most recent report by Lazarov et al. [25], however, showed that exposure of the APPswe/PS1DE9 transgenic mice to EE results in pronounced reductions in cerebral Ab levels and amyloid deposits compared to controls in standard housing. Further to their demonstration above, Lazarov et al., had directly zoomed in on a possible mechanistic explanation for EE induced reduction of amyloid burden by checking the activity of two known amyloid clearing protease–neprilysin [26] and the insulin degrading enzyme [27]. The authors showed that neprilysin activity is significantly elevated in the brains of the environmentally enriched mice compared to both non-transgenic controls and transgenic mice in standard housing. Backing up these specific analyses with global gene profiling, it was also shown that EE elevates the expression of some immediate early genes and others that encode neurogenic or neuroprotective products.
Environmental enrichment and ParkinsonÕs disease Physical activity has been associated with a reduced risk for ParkinsonÕs disease (PD) in humans [28]. Physical exercise in the form of motorized treadmill running improves the neurochemical and behavioral outcomes in two rodent models of PD: the unilateral 6-hydroxydopamine (6-OHDA) rat model and bilateral 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in mice [29]. In two recent analyses [30,31], mice raised in an enriched environment appear to be significantly more resistant to MPTP neurotoxicity than control mice.
L. Li, B.L. Tang / Biochemical and Biophysical Research Communications 334 (2005) 293–297
After MPTP treatment, Bezard et al., observed that enriched mice showed only a 40% loss in dopaminergic neurons compared to a 75% loss in controls. Both groups observed that enriched mice showed a reduced dopamine transporter activity or levels, with a contrasting increase in striatal BDNF levels. In a separate analysis using rats, environmental enrichment significantly decreased cell surface expression of dopamine transporter in the medial prefrontal cortex [32]. These data provide a direct demonstration of the beneficial consequences of an enriched environment on disease onset and progression in rodent models of ParkinsonÕs disease.
What benefits does environmental enrichment confer to the degenerating brain? There appear, at least superficially, some beneficial changes that are clearly associated with EE. Short term changes resulting from growth factor action and neural transmission are presumably simply neuroprotective. Daily voluntary wheel-running activity in rats, for example, increases the levels of the antiapoptotic phosphatidylinositol 3-kinase, Akt, and the downstream cAMP response element binding protein (CREB) [33]. Longer term changes would involve alterations in gene expression profiles in the neurons and glial cells at the respective regions of the brain, especially those sites of particular susceptibility to death of specific neurons in the various neurodegenerative diseases. The main problem with the significance of the data obtained from gene profiling analysis is of course the difficulty in animal standardization, because of the need to use animals of the different disease models in the first place. Mice with different genetic backgrounds respond differently. Worse, genetically ‘‘defective’’ mice with the onset (or susceptibility to onset) of a particular neurodegenerative disease may have significantly different gene expression profiles to begin with. As an illustration of the point in question, the identity of the genes that are found to be significantly elevated by Lazarov et al. [25] is almost a completely different set from those identified earlier by Rampon et al. [34] using non-Alzheimic mice. There is one notable overlap in terms of gene identity— the immediate early transcription factor c-fos, which is of interest because there is evidence for its role in neuronal excitability and survival [35]. However, while Lazarov et al., found that the level of c-fos is elevated after a 3-month period, Rampon et al., recorded a decline after 14 days of EE treatment. The difference in mice strain and details of EE regime could always be blamed for such contrastingly opposite results for any gene. In any case, do the gene products that are elevated or reduced as a result of EE have any influence on disease onset or outcome? The major problems in coming up with definitive answers to the above question are the
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following. The first is that we are lacking in quantitative appreciation of the changes in terms of significance threshold, i.e., what level of changes would actually influence disease pathology and what would have negligible effects? Is the elevation in neprilysin levels merely correlated with the degree of amyloid deposition, or it is actually significantly responsible for the difference (in terms of disease onset and progression) between control and EE mice? Likewise, at this moment we cannot yet be certain that the reduction in dopamine transporter expression in EE mice is responsible for the presumably lower susceptibility to MPTP. A second problem is a lack of understanding of the physiological, particularly neurophysiological function, of many of the genes identified. For several of these which are transcription factors, the range of other genes under their influences is often not known in any detail. The above problems are clearly those that could only be properly tackled with the vigor of a Systems Biology approach, with detail and elaborate expression profiling in standardized settings. A particular aspect of potentially clinical importance of EE is the physical exercise component. It is understandably difficult to isolate this component from the other aspects of a general EE regime. Earlier attempts to do so indicated that voluntary exercise is sufficient to enhance several aspects (including both survival and proliferation) of hippocampal neurogenesis in adult mice [7]. Lazarov et al., also showed that mice with higher levels of physical activity have a significantly lower level of amyloid deposition. For this correlation to be of value, more controlled experiments are needed to eliminate the chicken and egg possibility—that mice with a heavier amyloid load to begin with are less active. A more recently published study had also explored the effect of voluntary exercise, which decreased amyloid load in a different mice AD model [36]. The authors found that mice subjected to a cage equipped with a running wheel showed no changes in neprilysin or insulin degrading enzyme, but the decrease in amyloid load compared to control could be attributed to a decrease in APP processing, illustrated by a reduction in the a and b—C-terminal fragments (CTF). The difference in terms of upregulation in neprilysin is apparent. However, because a different mice model is used, we need not look too hard into the differences in the finding between this and the earlier study. One should also note that significant amount of physical exercise has an effect on blood cholesterol levels, and the latter has a significant correlation (albeit controversial) with brain Ab levels [37].
Implications on the animal model findings in human neurodegenerative diseases How would the observations described above be useful for both investigations and treatment of the human
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diseases? It may be disconcerting to note that the average human already has a much more enriched environment than an average laboratory mouse. Therefore, one could ask how much more ‘‘enriched’’ should oneÕs environment be in order to discern notable benefits from the onset and severity of neurodegenerative diseases. The benefits of an active social and intellectual lifestyle are well known, and formal and quantitative studies are well within the realm of clinical neuroscience. This is especially so with quantifiable regimes such as the amount and intensity of physical exercise. In view of the development of the rate of advances in non-invasive methods for imaging developing Alzheimic plaques [38,39], the most informative experiments may actually be the ones performed in the controlled settings of clinical trials with human subjects.
References [1] L. Fratiglioni, S. Paillard-Borg, B. Winblad, An active and socially integrated lifestyle in late life might protect against dementia, Lancet Neurol. 3 (2004) 343–353. [2] H. Van Praag, G. Kempermann, F.H. Gage, Neural consequences of environmental enrichment, Nat. Rev. Neurosci. 1 (2000) 191– 198. [3] M.P. Mattson, W. Duan, J. Lee, Z. Guo, Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms, Mech. Ageing Dev. 122 (2001) 757–778. [4] B. Will, R. Galani, C. Kelche, M.R. Rosenzweig, Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training (1990–2002), Prog. Neurobiol. 72 (2004) 167–182. [5] G. Kempermann, H.G. Kuhn, F.H. Gage, More hippocampal neurons in adult mice living in an enriched environment, Nature 386 (1997) 493–495. [6] G. Kempermann, D. Gast, F.H. Gage, Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by longterm environmental enrichment, Ann. Neurol. 52 (2002) 135–143. [7] H. Van Praag, G. Kempermann, F.H. Gage, Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus, Nat. Neurosci. 2 (1999) 266–270. [8] G. Kempermann, E.P. Brandon, F.H. Gage, Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus, Curr. Biol. 8 (1998) 939–942. [9] D. Young, P.A. Lawlor, P. Leone, M. Dragunow, M.J. During, Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective, Nat. Med. 5 (1999) 448–453. [10] B.R. Ickes, T.M. Pham, L.A. Sanders, D.S. Albeck, A.H. Mohammed, A.C. Granholm, Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain, Exp. Neurol. 164 (2000) 45–52. [11] C. Rampon, Y.P. Tang, J. Goodhouse, E. Shimizu, M. Kyin, J.Z. Tsien, Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice, Nat. Neurosci. 3 (2000) 238–244. [12] C. Landles, G.P. Bates, Huntingtin and the molecular pathogenesis of HuntingtonÕs disease, EMBO Rep. 5 (2004) 958–963. [13] A. Van Dellen, C. Blakemore, R. Deacon, D. York, A.J. Hannan, Delaying the onset of HuntingtonÕs in mice, Nature 404 (2000) 721–722.
[14] E. Hockly, P.M. Cordery, B. Woodman, A. Mahal, A. Van Dellen, C. Blakemore, C.M. Lewis, A.J. Hannan, G.P. Bates, Environmental enrichment slows disease progression in R6/2 HuntingtonÕs disease mice, Ann. Neurol. 51 (2002) 235–242. [15] M. Glass, M. Dragunow, R.L. Faull, The pattern of neurodegeneration in HuntingtonÕs disease: a comparative study of cannabinoid, dopamine, adenosine and GABAA receptor alterations in the human basal ganglia in HuntingtonÕs disease, Neuroscience 97 (2000) 505–519. [16] M. Glass, A. Van Dellen, C. Blakemore, A.J. Hannan, R.L. Faull, Delayed onset of HuntingtonÕs disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors, Neuroscience 123 (2004) 207–212. [17] C. Zuccato, A. Ciammola, D. Rigamonti, B.R. Leavitt, D. Goffredo, L. Conti, M.E. MacDonald, R.M. Friedlander, V. Silani, M.R. Hayden, T. Timmusk, S. Sipione, E. Cattaneo, Loss of huntingtin-mediated BDNF gene transcription in HuntingtonÕs disease, Science 293 (2001) 493–498. [18] L.R. Gauthier, B.C. Charrin, M. Borrell-Pages, J.P. Dompierre, H. Rangone, F.P. Cordelieres, J. De Mey, M.E. MacDonald, V. Lessmann, S. Humbert, F. Saudou, Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules, Cell 118 (2004) 127–138. [19] C.A. Altar, N. Cai, T. Bliven, M. Juhasz, J.M. Conner, A.L. Acheson, R.M. Lindsay, S.J. Wiegand, Anterograde transport of brain-derived neurotrophic factor and its role in the brain, Nature 389 (1997) 856–860. [20] C.A. Turner, M.H. Lewis, Environmental enrichment: effects on stereotyped behavior and neurotrophin levels, Physiol. Behav. 80 (2003) 259–266. [21] T.L. Spires, H.E. Grote, N.K. Varshney, P.M. Cordery, A. VanDellen, C. Blakemore, A.J. Hannan, Environmental enrichment rescues protein deficits in a mouse model of HuntingtonÕs disease, indicating a possible disease mechanism, J. Neurosci. 24 (2004) 2270–2276. [22] F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia, R. Malinow, APP processing and synaptic function, Neuron 37 (2003) 925–937. [23] J.L. Jankowsky, G. Xu, D. Fromholt, V. Gonzales, D.R. Borchelt, Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease, J. Neuropathol. Exp. Neurol. 62 (2003) 1220–1227. [24] G.W. Arendash, M.F. Garcia, D.A. Costa, J.R. Cracchiolo, I.M. Wefes, H. Potter, Environmental enrichment improves cognition in aged AlzheimerÕs transgenic mice despite stable beta-amyloid deposition, Neuroreport 15 (2004) 1751–1754. [25] O. Lazarov, J. Robinson, Y.P. Tang, I.S. Hairston, Z. KoradeMirnics, V.M. Lee, L.B. Hersh, R.M. Sapolsky, K. Mirnics, S.S. Sisodia, Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice, Cell 120 (2005) 701–713. [26] A.J. Turner, R.E. Isaac, D. Coates, The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function, Bioessays 23 (2001) 261–269. [27] W. Farris, S. Mansourian, Y. Chang, L. Lindsley, E.A. Eckman, M.P. Frosch, C.B. Eckman, R.E. Tanzi, D.J. Selkoe, S. Guenette, Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo, Proc. Natl. Acad. Sci. USA 100 (2003) 4162–4167. [28] H. Chen, S.M. Zhang, M.A. Schwarzschild, M.A. Hernan, A. Ascherio, Physical activity and the risk of Parkinson disease, Neurology 64 (2005) 664–669. [29] J.L. Tillerson, W.M. Caudle, M.E. Reveron, G.W. Miller, Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of ParkinsonÕs disease, Neuroscience 119 (2003) 899–911. [30] E. Bezard, S. Dovero, D. Belin, S. Duconger, V. Jackson-Lewis, S. Przedborski, P.V. Piazza, C.E. Gross, M. Jaber, Enriched
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[31]
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environment confers resistance to 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors, J. Neurosci. 23 (2003) 10999–11007. C.J. Faherty CJ, K.R. Shepherd, A. Herasimtschuk, R.J. Smeyne, Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism, Brain. Res. Mol. Brain Res. 134 (2005) 170–179. J. Zhu, S. Apparsundaram, M.T. Bardo, L.P. Dwoskin, Environmental enrichment decreases cell surface expression of the dopamine transporter in rat medial prefrontal cortex, J. Neurochem. 93 (2005) 1434–1443. M.J. Chen, A.A. Russo-Neustadt, Exercise activates the phosphatidylinositol 3-kinase pathway, Mol. Brain Res. 135 (2005) 181–193. C. Rampon, C.H. Jiang, H. Dong, Y. Tang, D.J. Lockhart, P.G. Schultz, J.Z. Tsien, Y. Hu, Effects of environmental enrichment on gene expression in the brain, Proc. Natl. Acad. Sci. USA 97 (2000) 12880–12884.
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[35] J. Zhang, D. Zhang, J.S. McQuade, M. Behbehani, J.Z. Tsien, M. Xu, c-fos regulates neuronal excitability and survival, Nat. Genet. 30 (2002) 416–420. [36] P.A. Adlard, V.M. Perreau, V. Pop, C.W. Cotman, Voluntary exercise decrease amyloid load in a transgenic model of AlzheimerÕs disease, J. Neurosci. 25 (2005) 4217–4221. [37] M. Michikawa, Cholesterol paradox: is high total or low HDL cholesterol level a risk for AlzheimerÕs disease? J. Neurosci. Res. 72 (2003) 141–146. [38] M. Higuchi, N. Iwata, Y. Matsuba, K. Sato, K. Sasamoto, T.C. Saido, 19F and 1H MRI detection of amyloid beta plaques in vivo, Nat. Neurosci. 8 (2005) 527–533. [39] M. Hintersteiner, A. Enz, P. Frey, A.L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K.H. Wiederhold, H.U. Gremlich, In vivo detection of amyloidbeta deposits by near-infrared imaging using an oxazine-derivative probe, Nat. Biotechnol. 23 (2005) 577–583.
Breakthroughs and Views
Environmental enrichment and neurodegenerative diseases Lingzhi Li, Bor Luen Tang * Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore Received 17 May 2005 Available online 9 June 2005
Abstract Recent reports on experimental models of neurodegeneration in mice have strengthened the notion that environmental enrichment (EE) is beneficial, in terms of delayed onset and progression, to a variety of neurodegenerative diseases. These studies also revealed interesting mechanistic understandings as to how EE might function. While it is generally assumed that EE elicits transcriptional and translational events that on the whole tend to be neuroprotective and neurogenic, fairly specific changes that appear to target the underlying pathological causes of disease in these various mouse models have been noted. These include a possible restoration of brain-derived neurotrophic factor striatal transport in the R6/1 HuntingtonÕs mice and an elevation in the levels of amyloid-degrading enzyme neprilysin in the APPswe/PS1DE9 Alzheimic mice. An elevation in glial-derived neurotrophic factor coupled to a reduction in dopamine transporter may underlie beneficial effects in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced Parkinsonian symptoms. How all these findings would translate to disease settings in human patients are unclear, but they do provide useful leads for further clinical and paraclinical investigations. Ó 2005 Elsevier Inc. All rights reserved. Keywords: AlzheimerÕs disease; Environmental enrichment; HuntingtonÕs disease; ParkinsonÕs disease
Maintenance of a socially and intellectually active lifestyle helps the elderly in maintaining their mental health. This notion is supported by numerous longitudinal data on the association of lifestyles with dementia (reviewed in [1]). This general idea also has good support from experimental animal models of human neurodegeneration, aging, and brain injury [2–4]. In a broad sense, environmental enrichment (EE) is an experimental paradigm in animals which supposedly parallel physical, social, and intellectual activity of humans. These include encouragements to perform physical exercise (e.g., running wheels) and exposure to a variety of passive visual stimuli (e.g., changing colored backgrounds and objects). EE may be beneficial to postnatal neuronal functions and survival in two general ways. First, EE is clearly neurogenic. Gage and co-workers [5,6] have extensively documented that mice exposed to an enriched environ*
Corresponding author. Fax: +65 67791453. E-mail address: [email protected] (B.L. Tang).
0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2005.05.162
ment have significantly more hippocampal neurons compared with those in standard housing, and that EE induces cell proliferation and neurogenesis at the dentate gyrus [7,8]. Second, EE elicits neuroprotective responses, largely in the form of elevation of neurotrophic factors in areas of the brain [9,10]. Furthermore, EE may induce synaptic structural changes that enhance learning and memory [5,11]. A number of recent reports with more elaborate mechanistic investigations have revealed, in each case, some cellular and molecular changes associated with EE that are more model specific. We summarize these observations in the following paragraphs, and ponder on how these may aid clinical and paraclinical investigations in human patients. Environmental enrichment and HuntingtonÕs disease HuntingtonÕs disease (HD) is an autosomal dominant inherited disease belonging to the general group of
294
L. Li, B.L. Tang / Biochemical and Biophysical Research Communications 334 (2005) 293–297
inherited neurodegenerative disorders characterized by an expansion of polyglutamine tracts, which in the case of HD is found in the protein hungtingtin [12]. Several transgenic mice models have been developed that recapitulate the progressive cognitive and motor symptoms of HD. Earlier studies have shown that subjecting the popular HD models, the R6/1 mice expressing exon 1 of huntingtin with an expanded number of glutamine repeats, to an enriched environment from four weeks significantly delayed the onset of disease symptoms and degenerative loss of cerebral volume without apparently reducing the formation of striatal neuronal inclusions typical of HD [13]. These beneficial effects are also observed with the R6/2 line with fast disease onset [14]. How exactly does EE act in a way that is beneficial to the HD mice? Human HD brain suffers from a lost of neurotransmitter receptors. Particularly severe loss occurs with the cannabinoid CB1 receptors, which are selectively lost from the basal ganglia output nuclei even prior to onset of disease symptoms [15]. This loss is apparently delayed in mice exposed to EE [16]. One neurotrophic factor that is consistently associated with HD is BDNF. Earlier reports suggest that huntingtin promotes BDNF transcription, and mutant huntingtin loses this function [17]. A recent finding further implicated huntingtin in mediating another aspect of BDNF functionality—its axonal transport. Huntingtin apparently enhances vesicle transport of BDNF along microtubule [18], and BDNF transport is impaired with a loss of functional huntingtin. BDNF is not synthesized at the striatum but are rather transported into it from the anterior cortex via axonal projections [19]. EE has been shown to elevate BDNF levels rather specifically in the striatum of deer mice [20]. In the R6/1 HD model, there is severe reduction of BDNF levels at the striatum, but not the anterior cortex. EE exposure reversed this reduction in striatal BDNF [21]. This suggests that the effect of EE in this case may be to alleviate the block in BDNF transport to the striatum. This block in BDNF transport is specific as nerve growth factor (NGF) levels were unaffected in the striatum in these animals. EE may also delay the deficits of certain key proteins in the HD model. One such protein whose level is reduced by about a quarter in both the striatum and anterior cortex of HD mice is the 32 kDa cAMP-regulated phosphoprotein (DARPP-32), a key regulator of dopamine and serotonin signaling. Interestingly, EE exposure does little to striatal DARPP-32 levels but elevates it in HD mice. The benefit of EE on HD disease onset and progression may therefore involve both transcriptional and post-transcriptional mechanisms.
Environmental enrichment and AlzheimerÕs disease AlzheimerÕs disease (AD) is the most prominent cause of age-related dementia. As mentioned above, a good
number of epidemiological studies have inferred a correlation between AD and intellectual, educational, and social background [1]. The pathophysiology of idiopathic AD is complex, but may in many cases involve neuronal stress and death cause by both soluble and aggregated forms of amyloid-beta (Ab) derived from amyloidegenic processing of the amyloid precursor protein (APP). It was shown using organotypic hippocampal slices prepared from an APP mutant (APPswe) transgenic mice that Ab production is apparently modulated by neuronal activity [22]. Although the experimental setting is fairly in vitro, it provided the first indication that there may indeed be a discernible mechanism that could possibly explain the beneficial effects of cognitively intense activities. It is therefore a little surprising when it was reported that APPswe/PS1DE9 (double-transgenic for mutant APP and presenilin 1, a key component of c-secretase) mice exposed to a short term (several months) enriched environment instead showed an increase in aggregated and total Ab compared to controls in standard caging [23]. In another study, long term EE seems to result in global, overall improvement in cognitive functions, but without decreasing Ab deposition [24]. A most recent report by Lazarov et al. [25], however, showed that exposure of the APPswe/PS1DE9 transgenic mice to EE results in pronounced reductions in cerebral Ab levels and amyloid deposits compared to controls in standard housing. Further to their demonstration above, Lazarov et al., had directly zoomed in on a possible mechanistic explanation for EE induced reduction of amyloid burden by checking the activity of two known amyloid clearing protease–neprilysin [26] and the insulin degrading enzyme [27]. The authors showed that neprilysin activity is significantly elevated in the brains of the environmentally enriched mice compared to both non-transgenic controls and transgenic mice in standard housing. Backing up these specific analyses with global gene profiling, it was also shown that EE elevates the expression of some immediate early genes and others that encode neurogenic or neuroprotective products.
Environmental enrichment and ParkinsonÕs disease Physical activity has been associated with a reduced risk for ParkinsonÕs disease (PD) in humans [28]. Physical exercise in the form of motorized treadmill running improves the neurochemical and behavioral outcomes in two rodent models of PD: the unilateral 6-hydroxydopamine (6-OHDA) rat model and bilateral 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in mice [29]. In two recent analyses [30,31], mice raised in an enriched environment appear to be significantly more resistant to MPTP neurotoxicity than control mice.
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After MPTP treatment, Bezard et al., observed that enriched mice showed only a 40% loss in dopaminergic neurons compared to a 75% loss in controls. Both groups observed that enriched mice showed a reduced dopamine transporter activity or levels, with a contrasting increase in striatal BDNF levels. In a separate analysis using rats, environmental enrichment significantly decreased cell surface expression of dopamine transporter in the medial prefrontal cortex [32]. These data provide a direct demonstration of the beneficial consequences of an enriched environment on disease onset and progression in rodent models of ParkinsonÕs disease.
What benefits does environmental enrichment confer to the degenerating brain? There appear, at least superficially, some beneficial changes that are clearly associated with EE. Short term changes resulting from growth factor action and neural transmission are presumably simply neuroprotective. Daily voluntary wheel-running activity in rats, for example, increases the levels of the antiapoptotic phosphatidylinositol 3-kinase, Akt, and the downstream cAMP response element binding protein (CREB) [33]. Longer term changes would involve alterations in gene expression profiles in the neurons and glial cells at the respective regions of the brain, especially those sites of particular susceptibility to death of specific neurons in the various neurodegenerative diseases. The main problem with the significance of the data obtained from gene profiling analysis is of course the difficulty in animal standardization, because of the need to use animals of the different disease models in the first place. Mice with different genetic backgrounds respond differently. Worse, genetically ‘‘defective’’ mice with the onset (or susceptibility to onset) of a particular neurodegenerative disease may have significantly different gene expression profiles to begin with. As an illustration of the point in question, the identity of the genes that are found to be significantly elevated by Lazarov et al. [25] is almost a completely different set from those identified earlier by Rampon et al. [34] using non-Alzheimic mice. There is one notable overlap in terms of gene identity— the immediate early transcription factor c-fos, which is of interest because there is evidence for its role in neuronal excitability and survival [35]. However, while Lazarov et al., found that the level of c-fos is elevated after a 3-month period, Rampon et al., recorded a decline after 14 days of EE treatment. The difference in mice strain and details of EE regime could always be blamed for such contrastingly opposite results for any gene. In any case, do the gene products that are elevated or reduced as a result of EE have any influence on disease onset or outcome? The major problems in coming up with definitive answers to the above question are the
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following. The first is that we are lacking in quantitative appreciation of the changes in terms of significance threshold, i.e., what level of changes would actually influence disease pathology and what would have negligible effects? Is the elevation in neprilysin levels merely correlated with the degree of amyloid deposition, or it is actually significantly responsible for the difference (in terms of disease onset and progression) between control and EE mice? Likewise, at this moment we cannot yet be certain that the reduction in dopamine transporter expression in EE mice is responsible for the presumably lower susceptibility to MPTP. A second problem is a lack of understanding of the physiological, particularly neurophysiological function, of many of the genes identified. For several of these which are transcription factors, the range of other genes under their influences is often not known in any detail. The above problems are clearly those that could only be properly tackled with the vigor of a Systems Biology approach, with detail and elaborate expression profiling in standardized settings. A particular aspect of potentially clinical importance of EE is the physical exercise component. It is understandably difficult to isolate this component from the other aspects of a general EE regime. Earlier attempts to do so indicated that voluntary exercise is sufficient to enhance several aspects (including both survival and proliferation) of hippocampal neurogenesis in adult mice [7]. Lazarov et al., also showed that mice with higher levels of physical activity have a significantly lower level of amyloid deposition. For this correlation to be of value, more controlled experiments are needed to eliminate the chicken and egg possibility—that mice with a heavier amyloid load to begin with are less active. A more recently published study had also explored the effect of voluntary exercise, which decreased amyloid load in a different mice AD model [36]. The authors found that mice subjected to a cage equipped with a running wheel showed no changes in neprilysin or insulin degrading enzyme, but the decrease in amyloid load compared to control could be attributed to a decrease in APP processing, illustrated by a reduction in the a and b—C-terminal fragments (CTF). The difference in terms of upregulation in neprilysin is apparent. However, because a different mice model is used, we need not look too hard into the differences in the finding between this and the earlier study. One should also note that significant amount of physical exercise has an effect on blood cholesterol levels, and the latter has a significant correlation (albeit controversial) with brain Ab levels [37].
Implications on the animal model findings in human neurodegenerative diseases How would the observations described above be useful for both investigations and treatment of the human
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diseases? It may be disconcerting to note that the average human already has a much more enriched environment than an average laboratory mouse. Therefore, one could ask how much more ‘‘enriched’’ should oneÕs environment be in order to discern notable benefits from the onset and severity of neurodegenerative diseases. The benefits of an active social and intellectual lifestyle are well known, and formal and quantitative studies are well within the realm of clinical neuroscience. This is especially so with quantifiable regimes such as the amount and intensity of physical exercise. In view of the development of the rate of advances in non-invasive methods for imaging developing Alzheimic plaques [38,39], the most informative experiments may actually be the ones performed in the controlled settings of clinical trials with human subjects.
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