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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD The Search for Novel Avenues for the Therapy and Prevention of Alzheimer's Disease. The Search for Novel Avenues for the Therapy and Prevention of Alzheimer's Disease by Christian Behl Summary The prevention and therapy of neurodegenerative disorders in the elderly is one of the greatest challenges facing molecular medicine today. Alzheimer's is an excellent example of a disease being studied by many groups worldwide. Indeed, while many molecular details of this disorder have been elucidated in the last two decades, there are still no strictly causal therapies available. While certain symptomatic pharmacological treatments are frequently employed, current molecular medicine research is focused on central Alzheimer-associated biochemical changes to find the key switch that turns the detrimental Alzheimer process on. Although amyloid β proteins and τ proteins are the focus of most investigations, intracellular signaling has recently gained a lot of attention as well. Signaling mediated by glycogen synthase kinase is intensively studied since it is a survival factor for neurons, is directly linked to Alzheimer-specific pathobiochemistry, and its activity can be modulated by well-known neuroprotective factors such as the female sex hormone estrogen. © 2006 Prous Science. All rights reserved. Dramatic shifts in societal age demographics in industrialized countries pose a challenge to molecular medicine in providing preventative treatments and therapies against age-associated disorders. Among the degenerative disorders of the nervous system Alzheimer’s disease (AD) is the most prominent and important. Although described about one hundred years ago by Alois Alzheimer, there is still no full understanding of its pathogenesis, and consequently no causal therapy is available. With the improvement of modern technologies in molecular biology, however, more details regarding the pathobiochemical mechanisms in AD have been deciphered, and there is intensive work ongoing to address certain AD-associated pathways as pharmaceutical targets for preventive and therapeutic treatments. Among all AD cases two different types can be distinguished. A minor proportion (approximately 5%) is comprised of genetic forms of AD that follow a strict autosomal-dominant inheritance. For this type of AD, three genes have been described, which when mutated, lead to the development of AD. These genes are the amyloid precursor protein (APP), the presenilin-1 (PS1) and the presenilin-2 (PS2) genes.1 However, the majority of all AD cases is age-related. In addition, while the pathways of pathogenesis may be influenced by certain vulnerability genes, age remains the only definitive risk factor for these AD cases.2 Although AD can therefore be differentiated into these two disease types (genetic versus nongenetic/age-related), the neuropathological hallmarks of both forms are almost identical. The brain of an AD patient shows at least three clear signs of neurodegeneration: dysfunctional, dystrophic neurites, intracellular neurofibrillary tangles (NFT) and extracellular de-posits of the amyloid β protein (Aβ). The two biochemical hallmarks, NFTs and Aβ, are at the center of research efforts to clarify the real cause of AD.1,2 Besides these two molecular aberrations, there are many additional changes occurring in neurotransmission and neuronal cell function. For instance, levels of certain neuropeptides (e.g., corticotropin-releasing hor-mone, CRH) and neurotransmitters (acetylcholine, ACh) are decreased. Some current and experimental approaches for AD therapy Currently, the primary therapy for AD is to stabilize acetylcholine levels, thereby improving cholinergic neurotransmission since one of the first changes observed during AD pathogenesis is a massive decrease in cholinergic transmissions.3 The trick is to block the enzyme degrading acetylcholine in the synaptic cleft, which results in increased levels of acetylcholine and enhanced neurotransmission. Such inhibitors of acetylcholine esterase have been developed and currently at least four different types are approved for use in the United States bearing the trade names tacrine, donepezil, rivastigmine and galantamine. Some of them are selective inhibitors of acetylcholine este-rase. Galantamine is also an allosteric ligand of the nicotinic acetylcholine receptor.4 In focusing on the therapeutic success of this approach, a recent meta-analysis showed that while acetylcholine esterase inhibitors have been frequently used in a variety of short-term clinical studies, an extended study analyzing the long-term efficacy of these antidementia drugs remains untried.5 In addition, it is not clear at this time whether these compounds do indeed increase the life span of patients suffering from AD. Consequently, the use of acetylcholine esterase inhibitors in AD is still under intense investigation.5,6 Another pharmaceutical target in AD therapy is glutamatergic neurotransmission, since it is clear that glutamate-driven signaling is central to the process of long-term potentiation (LTP), a mechanism regarded as central to learning and memory in the mammalian brain.7,8 Indeed, overactivation of glutamate receptors, and N-methyl-D-aspartate (NMDA) receptors in particular, can induce neurotoxic events ultimately leading to nerve cell death.9 Since a rise in intracellular calcium, as induced following NMDA receptor activation, is also known to cause AD tissue and NMDA receptor dysfunction, it has been directly and indirectly implicated in AD pathogenesis. Moreover, the NMDA receptor system is, of course, a target for AD therapy and prevention. A compound that acts as a noncompetitive NMDA antagonist was initially tested in experimental ische-mia. This drug is called memantine and displays a medium affinity for the NMDA receptor at specific binding sites. Memantine can block glutamate-mediated neurotoxic events while at the same time leaving the physiological activation of the NMDA receptor during physiological neurotransmission unchanged.10 Subse-quently, memantine was approved for use in clinical studies and several such investigations have followed. Curren-tly, it is not really clear whether memantine really interferes with the early AD disease process or if me-mantine really is a promising AD compound.11 Some initial positive effects of memantine in AD patients have been observed. While the therapeutic approaches mentioned so far are in clinical use as specific AD drugs, additional AD-associated pathobiochemical changes have also been detected, and are under investigation as potential clues to AD therapy and prevention. Among these is a strategy to affect τ protein changes in AD. A recent study by Santacruz et al. strongly supports a central role for neurofibrillary tangles and τ function disturbances in AD since suppression of tau has been shown to improve memory function in a neurodegenerative mouse model.12 Oxidations have been frequently observed to occur in neurodegenerative events, leading to the formulation of a hypothesis centered upon oxidative stress. Consequently, the importance of antioxidants for AD prevention has been stressed by many labs and various antioxidant molecules including vitamin E (α-tocopherol) and vitamin C (ascorbate) have been used in clinical trials.13 In a very recent clinical study the combined use of vitamin E and vitamin C supplements was associated with the reduced prevalence and incidence of AD, raising hope that the use of antioxidants could perhaps offer one way to prevent AD.14 Of course, it must be stressed that the use of antioxidants is not a specific tool for AD, but rather represents a general way of stabilizing the viability and resistance of neuronal tissue. Nonetheless, other experimental approaches for the prevention and treatment of AD have been suggested including the use of sex hormones via hormone replacement.15,2 The majority of research efforts aimed at developing an effective routine therapy for AD are still based on an antiamyloid approach. The biochemical processing of APP can be divided into amyloidogenic and antiamyloidogenic pathways (Fig. 1). In the amyloidogenic pathway, APP can be cleaved by the aspartyl protease BACE, the so-called β-secretase that generates the N-terminus of Aβ and soluble N-terminal derivative APPs-β. A subsequent cleavage at the remaining 99 amino acid C-terminal fragment (C99) within the transmembrane region produces Aβ from APP which is released.16 This cleavage event, which occurs inside the membrane, has been called γ-secretase activity and requires a complex association of various proteins including presenilin. Mutations within presenilin-1 are the most common genetic cause of familial AD.17 Aβ peptides (especially the slightly longer Aβ42 peptide) can easily aggregate, form oligomers and ultimately be deposited in tissues, leading to the formation of so-called senile plaques. The antiamyloidogenic pathway is characterized by a secretase activity that cleaves the APP molecule in the middle of the Aβ sequence, releasing a soluble APP-α fragment (APPs-α). The enzyme is therefore called α-secretase.19 Within the membrane an 83 amino acid (C83) remains, which is then emplaced by the γ-secretase complex, thereby releasing a P3 Aβ fragment that can no longer aggregate.1,19 Following the discovery of these molecular pathways and the different secretase activities (α, β, γ), a search for inhibitors of β- and γ-secretases has since been launched with the hope that an interruption of Aβ formation and aggregation will indeed prove the molecular way to block the development of AD.
Fig. 1. Amyloid precursor protein (APP) processing can be divided into amyloidogenic (A) and antiamyloidogenic pathways (B). In the amyloidogenic pathway, APP is cleaved by BACE1, the protease β-secretase. Cleavage occurs at the N-terminus of the Aβ domain and results in the secreted sAPPβ, as well as a C-terminal 99 amino acid fragment of APP(C99). C99 is further processed within its transmembrane domain by γ-secretase, leading to Aβ secretion and the generation of the APP intracellular domain (AICD). The Aβ peptide oligomerizes, leading to neurotoxicity. Aβ peptides are deposited in amyloid plaques (senile plaques), a pathological hallmark of AD. In the antiamyloidogenic pathway, APP is cleaved by α-secretase within the Aβ peptide domain, resulting in sAPPα as well as a C-terminal 83 amino acid fragment of APP(C83). C83 can also be processed by γ-secretase, thereby generating AICD. The consecutive cleavage events of APP by α-secretase constitute the antiamyloidogenic pathway as it inhibits Aβ generation (Figure modified from ref. 2). These antiamyloid approaches are still under intensive investigation and there is great hope that the interruption of the Aβ cascade and Aβ deposition may prevent neurodegeneration. In addition, several factors are known to modulate intracellular signaling pathways that are involved in τ phosphorylation and Aβ production; these may therefore be called neuroprotective factors. These include the female sex hormone estrogen, which displays a wide range of neuromodulatory and neuroprotective activities as described below, as well as intracellular signal mechanisms that have been associated with nerve cell survival. Glycogen synthase kinase-3β and AD pathogenesis Aβ is a prime suspect threatening neuronal survival while Aβ neurotoxicity has been described in a variety of experimental models such as in primary neuronal cultures of mouse, rat and human. Indeed, following its biochemical aggregation Aβ can directly interact with neuronal membranes, potentially interfering with neurotransmission and directly inducing oxidative stress in affected neurons.20,21 Aβ aggregates increase the oxidative burden on neurons by activating intracellular oxidases, which ultimately leads to the peroxidation of membranes and disintegration of the cells.22 This direct neurotoxicity has been shown mostly for primary and clonal cell cultures. Moreover, as intriguing as this Aβ neurotoxicity concept is, it is not fully consistent with the in vivo pathological situation presented in AD patients. Neverthe-less, Aβ neurotoxicity and morphological alterations in cultured neurons, including neuronal shrinkage and axonal and dendritic dystrophy, have been found in AD neurons also exhibiting neurofibrillar pathology.23 τProtein kinase 1/glycogen synthase kinase-3β (GSK-3β) in its enzymatic active form, as well as hyperphosphorylated τ protein and a general breakdown of the microtubular network, has been associated with the presence of Aβ peptides in cultured neurons.24,25 Among the group of kinases that phosphorylate proteins primarily at serine or threonine or proline motifs, the stress-activated kinase Jun N-terminal kinase (JNK) and the GSK-3β are well known. They have been shown to phosphorylate τ protein and generate AD-like antibody epitopes.26-29 Recent research has focused on GSK-3β, and it appears that this enzyme plays a major role in maintaining the stability of the τ protein and other mitogen activated proteins (MAPs).30,31 Therefore, GSK-3β activity has also been defined as a prime pharmacological target in AD since blocking GSK-3β activity may prevent tau hyperphosphorylation.32-35 As GSK-3β is obviously an important enzyme linked to τ phosphorylation, it is necessary to take a more detailed look at this enzyme. Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase that has been shown to inactivate the enzyme glycogen synthase via specific phosphorylation.36,37 Glycogen synthase itself is a key player in glycogen metabolism. In addition to its prominent role as a regulator of glycogen synthase, GSK-3 acts as a downstream regulator of various signaling pathways in the cell.38,39 After the discovery of disturbed intracellular signal transduction pathways in numerous human disorders and with the availability of specific molecular tools (e.g., phosphorylation-specific antibodies), GSK-3 expression and activity in the pathogenesis of diabetes, bipolar disorder, cancer and AD were investigated. The enzyme GSK-3 comes in two flavors in mammalian cells. The two isoforms of GSK-3 are GSK-3α and GSK-3β, which are encoded by two different genes.40 GSK-3α and GSK-3β are highly homologous proteins albeit with different functions. GSK-3α is 51 kDa and GSK-3β is 47 kDa in size. This size difference is due to a glycine-rich extension at the N-terminus of GSK-3α (Fig. 2). In eukaryotes, different GSK-3 homologues can be found displaying a high degree of homology. Interestingly, there is an over 90% sequence similarity when comparing GSK-3 isoforms from flies with those found in humans.41 The fact that GSK-3α and GSK-3β displays different functions has been clearly demonstrated by the lack of functional rescue through GSK-3α in GSK-3β knockout animal models.42 With respect to neuronal tissue and neurodegenerative events, GSK-3β has been studied intensively, as it is a major enzyme implicated in the phosphorylation of the τ protein.43,44
Fig. 2. Domain structure of mammalian GSK-3α and GSK-3β. Serine and tyrosine phosphorylation are indicated with arrowheads. The glycine-rich N-terminal domain is unique to GSK-3α and the conserved kinase domain is present in both GSK isoforms (Figure modified from Ref. 31). In addition to the τ protein, other substrates of GSK-3 have been described that can be linked to AD pathogenesis including presenilin-1 (PS1),45 β-catenin,46 cAMP response element binding protein,47 insulin receptor substrate-148 and others. It is strongly believed that the identification of GSK-3β substrates may provide knowledge about those specific signaling events that are altered during nerve cell death. Among those substrates associated with AD, the most interesting downstream targets of GSK-3β is, of course, the τ protein although β-catenin, a mediator of the Wnt signaling pathway and cell adhesion,49 is similarly worth investigating. While the effects of GSK-3β on glycogen metabolism and τ phosphorylation can directly be linked to AD-associated pathogenetic events, GSK-3β’s relation to Wnt signaling warrants discussion. Wnt signaling, an important mechanism involved in development and developmental disorders, has recently been linked to the pathogenesis of schizophrenia and AD.50-55 It has been found that familial AD-associated presenilin-1 proteins can form multiprotein complexes with the cell adhesion/signaling molecule β-catenin and GSK-3β.56-59 Clearly, β-catenin and GSK-3β are downstream members of the Wnt signaling pathway (Fig. 3). The results of expression studies suggest a direct role of β-catenin in AD since β-catenin levels appear to be significantly reduced in AD patients with PS1 mutations.56 At the cellular level, PS1 mutations have been found to directly disturb β-catenin translocation to the nucleus, thereby altering downstream Wnt signaling.60,61 Modulation of upstream Wnt signaling via a missing Wnt ligand may result in GSK-3β phosphorylation activity directed at β-catenin, which then becomes a target for ubiquitin proteosome degradation. In the presence of Wnt ligands, GSK-3β activity is inhibited via the disheveled protein. Consequently, β-catenin remains unphosphorylated and unable to translocate to the nucleus and induce transcriptional chan-ges.62-64 In addition to Wnt signaling’s involvement in AD-associated chan-ges, it has been recently proposed that Aβ-induced neurotoxin changes are linked not only to the Wnt signaling pathway, but also to the subsequent onset of mitosis in different neurons.49 Interestingly, there have also been reports that Wnt signaling and Aβ neurotoxicity are directly correlated.65,66
Fig. 3. Schematic representation of the Wnt/β-catenin signaling pathway and the effect of GSK-3β inhibitors. In the presence of the Wnt ligand, the Frizzled receptor (Fzd) in tandem with the LDL-related receptor protein (LRP5/6) mediates signal transduction by activating the Disheveled protein (Dvl). Dvl inactivates GSK-3β, which is part of a complex with APC, Axin and β-catenin proteins. Intracellular β-catenin levels increase and β-catenin may not only bind to the transcription factors Tcf/LEF, but also activate the transcription of Wnt target genes. Lithium (Li+) is a well-known general inhibitor of GSK-3 activity, as well as a pharmacological activator of Wnt target genes. Physiological inhibitors of GSK-3β activity include 17β-estradiol and corticotropin-releasing hormone (CRH). Consequently, the phosphorylation of the AD-related τ-protein at specific GSK-sites is prevented. When the Wnt ligand is absent, GSK-3β activity leads to the phosphorylation of β-catenin, marking this protein for ubiquitin-mediated degradation, and thereby inhibiting transcriptional activity as well as β-catenin translocation to the nucleus. Familial AD-associated presenilin-1 proteins (PS1) can form multiprotein complexes with β-catenin and GSK-3β. Returning to GSK-3β, it should be noted that GSK-3β expression and activity has generally been linked to nerve cell survival. It has been long known that GSK overexpression is sufficient to cause cell death in PC12 cells in vitro, as well as in transgenic mice in vivo.67,44 GSK appears to be critical in neurodegeneration resulting from numerous upstream insults including PI3 kinase inhibitors, serum deprivation or loss of trophic support.68-73 Inhibition of GSK-3β with pharmacological tools or by a dominant-negative GSK-3β expression construct appears to be neuroprotective in the applied models. Moreover, it has been shown that well-known neuroprotective molecules, including nerve growth factor (NGF) and those factors that increase intracellular cAMP levels, exert their protective activity through the inactivation of GSK-3β, specifically via the phosphorylation on serine 9 residues.67,70 In addition, lithium chloride (LiCl), the general inhibitor of GSK-3β, as well as more specific maleimide-derived inhibitors can induce increased neuronal cell survival when added to hippocampal slice cultures under oxidative stress.74 Posttranslational modification and specific binding proteins can block GSK-3β enzyme activity. In general, GSK-3β can be activated by phosphorylation at tyrosine residue 216; it can be inactivated either by dephosphorylation at tyrosine 216 or by phosphorylation at the serine 9 residues.75 Therefore, to summarize experimental data thus far, inactivation of GSK-3β (i.e., the inhibition of GSK-3β phosphorylation activity) appears to be a protective event. Recently, we have found that the female sex hormone estrogen, a well-known neuromodulator, inactivates GSK-3β activity. More specifically, estrogen can reduce the GSK-3β-mediated phosphorylation of τ as found in animals treated with estrogen.35 Estrogens have been long studied as important modulators of neuronal functions76 and in the last decade increasing evidence suggests that estrogens act as direct protective signals in the nervous system. Neuroprotection by estrogens is mediated via numerous intracellular pathways. Estradiol (estrogen) is a steroid molecule that acts via an intracellular nuclear estrogen receptor. Two estrogen receptor subtypes, ER-α and ER-β, both translocate to the nucleus, thereby changing gene transcription upon activation with the ligand estradiol.77 Various direct target genes of estrogen receptors exhibiting neuroprotective activities are known: brain-derived neurotrophic factor (BDNF), BCL-2 and others. In addition to these direct genomic effects of estrogen and estrogen receptor activity, estrogen can induce intracellular signaling pathways by the interaction of estrogen receptors localized at the membrane or cytoplasmic estrogen receptors directly associated with the intracellular molecules such as PI-3 kinase.15 With the recent finding that estrogen also affects GSK-3β activity, and therefore the activity of an enzyme that has been directly linked to nerve cell survival, an additional mode of neuroprotection exerted by estrogen has been found. Moreover, estradiol itself can act as a direct neuroprotective antioxidant due to its phenolic structure, as determined by many experimental models that did not involve activating estrogen receptors.78-80 In another recent study published by our lab, we found still another physiological factor that may affect GSK-3β activity. We have shown that corticotropin-releasing hormone (CRH), a main mediator of the human hypothalamic pituitary-adrenal-stress axis, may act as a neuroprotective factor at the molecular level.81,82 In a study employing primary neuronal cultures from rat and focusing on the brain area that features the specific signaling of CRH, we found that CRH inactivates GSK-3β in cortical neurons but not in cultures derived from the hippocampus or cerebellum.83 We have concluded that part of the neuroprotective activity of CRH may stem from the direct effect on GSK-3β activity. Since different physiological factors directly affect GSK-3β activity, which may then increase neuronal cell survival, we believe it would be worthwhile to develop high throughput screenings. This would assist the search for proteins and low-molecular-weight compounds that inactivate GSK-3β and which could be used as neuroprotective compounds for the prevention of neurodegeneration. References 1.- Selkoe, D.J. 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Mol Endocrinol 2000, 14: 147-59. 82.- Bayatti, N. and Behl, C. The neuroprotective actions of corticotropin releasing hormone. Ageing Res Rev 2005, 4: 258-70. 83.- Bayatti, N., Zschocke, J. and Behl, C. Brain region-specific neuroprotective action and signaling of corticotropin-releasing hormone in primary neurons. Endocrinology 2003, 144: 4051-60. Christian Behl is Chair of Biochemistry and Director of the Institute for Physiological Chemistry and Pathobiochemistry at the Johannes Gutenberg-University Mainz, Medical School. Correspondence: Institute for Physiological Chemistry & Pathobiochemistry, Johannes Gutenberg-University Mainz, Medical School, Duesbergweg 6, 55099 Mainz, Germany. E-mail: cbehl@uni-mainz.de. Drug News & Perspectives
Vol. 19, No. 1, 2006, pp. 5-12
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