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Current Alzheimer Research, 2007, 4, 21-31

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Glycogen Synthase Kinase-3 in Neurodegeneration and Neuroprotection: Lessons from Lithium Saeed Yadranji Aghdam1 and Steven W. Barger2,* 1

School of Biology, University of Tehran, Tehran 14155-6455, Iran; 2Departments of Geriatrics and Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock AR 72205 USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock AR 72205, USA Abstract: For over fifty years lithium has been a fundamental component of therapy for patients with bipolar disorders. Lithium has been considered recently for its potential to alleviate neuronal loss and other neurodegeneration processes. For instance, lithium reduces the severity of some behavioral complications of Alzheimer's disease (AD). And there are growing indications that lithium may be of benefit to the underlying pathology of AD, as well as an array of other common CNS disorders, including stroke, Parkinson's disease, and Huntington's disease. Despite these demonstrated and prospective therapeutic benefits, lithium’s mechanism of action remains elusive, and opinions differ regarding the most relevant molecular targets. Lithium inhibits several enzymes; significant among these are inositol monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3), and the proteasome. Most recent publications discussing the medical application of lithium have converged on GSK-3, so this article reviews data and discussions regarding the roles and interactions of GSK-3 with other proteins and its proposed role in the pathogenesis of Alzheimer's disease.

INTRODUCTION The breadth of physiological pathways impacted by glycogen synthase kinase-3 (GSK-3) is only now being appreciated. GSK-3 is a serine/threonine kinase that phosphorylates and inactivates glycogen synthase, and thus was originally known for its role in regulation of metabolism [1]. Specifically, insulin stimulates an inactivating phosphorylation of GSK-3 itself, thereby effecting an indirect disinhibition of glycogen synthase. More recently, GSK-3 was identified as a participant in the signal-transduction pathway regulated by ligands of the Wnt family, a signaling system critically involved in development and implicated in cancer and other diseases [2]. GSK-3 is a component of a multi-protein complex consisting of axin, -catenin, Dishevelled, and adenomatous polyposis coli (APC). In the absence of Wnt receptor activation, GSK-3 tonically phosphorylates -catenin, thereby targeting it for ubiquitin-mediated degradation (Fig. 1). Upon activation of the Wnt pathway via extracellular ligand binding, the pathway becomes active and Dishevelled disrupts the complex, preventing phosphorylation of catenin by GSK-3. Unphosphorylated -catenin then binds to transcription factors of the T-cell factor/lymphoid-enhancer factor (Tcf/Lef) family and activates the transcription of specific target genes [3]. This somewhat unusual “sign-change” type of activation by inhibition of an inhibitor (GSK-3) is therefore a common element of GSK-3 action in both the insulin and Wnt signaling pathways [4]. REGULATION OF GLYCOGEN SYNTHASE KINASE-3 BY LITHIUM AND PI3-K/AKT PATHWAY Two isoforms of GSK-3 ( and ) are encoded by separate genes but show 85% sequence homology [5]. In the rat *Address correspondence to this author at the Reynolds Institute on Aging, 629 Jack Stephens Dr., #807, Little Rock, AR 72205, USA; Tel: 501.526.5811; Fax: 501.526.5830; E-mail: [email protected] 1567-2050/07 $50.00+.00

CNS, GSK-3 is noticeable in late embryonic life and remains at its peak levels through several days of postnatal life [6]. It declines into adulthood, but relative to other tissues, brain expression of GSK-3 remains high even in the adult [7]. Neurons express GSK-3, while astrocytes do not [6]. Lithium is clearly able to inhibit directly both GSK-3 and GSK-3 [8], apparently by competing with magnesium [9]. Klein and coworkers [10] demonstrated that in vitro exposure of GSK-3 or GSK-3 to lithium or other smallmolecule inhibitors leads to increased serine phosphorylation of the enzymes at an autoregulatory aminoterminal position. This inhibitory serine phosphorylation of GSK-3 occurs to an even greater degree when it results from chronic treatment with lithium in vivo [11]. Another mechanism to account for the inhibition of GSK-3 involves the activation of phosphatidylinositide 3'OH kinase (PI3K)/Akt pathway, which is a survival-inducing pathway in most cell types; the activated Akt promotes phosphorylation and inactivation of GSK-3. Akt (also known as protein kinase B, or PKB) downregulates the activity of GSK-3 and GSK-3 by phosphorylating the former at residue serine 21 (Ser21) and the latter at residue serine 9 (Ser9) [12]. IGF-1 and insulin, emblematic agonists of the PI3K/Akt system, inhibit GSK-3 indirectly by promoting its phosphorylation on Ser-9 by Akt [13]. These physiological interactions may also be enlisted by pharmacological agents. Inhibition of GSK-3 with either lithium or a more specific inhibitor, (2'Z,3'E)-6-bromoindirubin-3'-oxime (BIO), was able to activate Wnt and PI3-K/Akt signaling pathways to promote survival in mouse proximal tubular cells [14]. This pathway may explain the rapid activation of PI3-K activity and attendant Akt phosphorylation evoked by lithium in cultured neurons [15] or the activation of Akt after exposure to lithium reported in the brains of treated mice [16]. ©2007 Bentham Science Publishers Ltd.

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Fig. (1). Lithium modulation of GSK-3 in general neuroprotective schema. Constitutive activity of GSK-3 phosphorylates -catenin, targeting it for proteasomal degradation and thereby reducing the levels of -catenin that would otherwise translocate to the nucleus and induce (in concert with cofactors like T-cell factors; Tcf) the transcription of prosurvival genes. GSK-3 also appears capable of activating Bax, which can activate the mitochondrial membrane permeability transition, permitting a flux of cytochrome c from the mitochondria to the cytosol where it activates caspase cascades. GSK-3 can be inhibited by phosphorylation by Akt, itself activated by PI3 kinase. GSK-3 is also inhibited by ligation of the Wnt receptor (Frizzled), which induces Dishevelled (dsh) to inactivate GSK-3. Lithium directly blocks GSK-3, thereby mimicking the effects of physiological signals. Other potential contributions of GSK-3 and lithium to cell death and survival mechanisms are detailed in the text.

LITHIUM AS A GENERAL NEUROPROTECTANT A wealth of evidence exists to point to the principal involvement of GSK-3 in the processes of neuronal apoptosis and neurodegeneration. Examples range from the physiologically appropriate forms of apoptosis that occur during development to the undesirable tissue damage that results from strokes and other instances of ischemia. The implications of pharmacological manipulation of such events for human health is manifest in the association of lithium therapy with an increase in the volume grey matter in bipolar patients, an effect linked to the neuroprotective properties of lithium [17]. During development, appropriate target innervation is partially governed by matching a trophic factor in the target with its receptors on in-growing afferent fibers. Thus, a neuron sending its primary process into an inappropriate target field will become starved for its preferred trophic factor, and the neuron will die, qualitatively eliminating an inappropriate connection. Similarly, excessive in-growth to a target can be regulated quantitatively by competition between the arriving fibers for a limited supply of trophic factor. These events

are modeled in cell culture through the removal of a trophic factor from a neuronal culture that depends on said factor for viability. With respect to the Wnt signaling pathway, it is rather obvious that sufficient supplies of ligand would suppress GSK-3 and its phosphorylation of -catenin, thereby freeing -catenin from degradation and allowing it to influence the transcription of genes. -catenin appears to generally enhance transcription of prosurvival genes and inhibit the expression of apoptotic genes. The dominant role of GSK-3 in neuronal cell death has been demonstrated though overexpression of GSK-3 in a human neuroblastoma cell line, which sensitized these cells to the proapoptotic effects of staurosporine or heat shock [18]. Similarly, similar overexpression of GSK-3 in vivo results in frank neurodegeneration [19]. Because lithium inhibits GSK-3, it essentially substitutes for Wnt ligands and thereby increases the nuclear translocation of -catenin [20]. Indeed, lithium can override the apoptotic effect of GSK-3 [18]. And apparently, the events initiated by lithium can be a dominant prosurvival process so that they protect against withdrawal of trophic factors unrelated to Wnt, as well [21]. For instance, lithium reduces

Glycogen Synthase Kinase-3 in Neurodegeneration

death of neurons induced by withdrawal of NGF [3] and KC [22]. Some of this ability to cross over to other signaling pathways may involve lithium’s activation of PI3-K/Akt survival signaling. Akt inactivates GSK-3 through phosphorylation at Serine 9 [13]. Transduction of survivalpromoting signals mediated by most of growth factors and neurotrophins is conducted through PI3-K/Akt signaling pathway, where the downstream target is GSK-3 [21, 23, 24]. Examples of this kind of regulation include the activation of PI3K/Akt and neuroprotection by FGF-1 [25] insulin [26], IGF-I, [27, 28], BDNF [29] and NGF [30]. Pro-apoptotic actions of GSK-3 appear to involve nuclear accumulation of the kinase [31-35]. This may be related to actions of GSK-3 that are independent of -catenin destabilization. GSK-3 has been shown to modulate the activity of other transcription factors through phosphorylation, including NFAT [36], CRMP-2 [37], p65 NFB [38], eIF2 [39], CREB [40], HSF-1 [41], c-Myc, p53, and c-Jun. Lithium can clearly influence the transcriptional activity of some of these transcription factors to promote cell survival. For instance, treatment of granule neurons with lithium inhibits GSK-3 and the nuclear export of NFAT3 to increase neuronal survival even under proapoptotic conditions [42]. Through inhibiting GSK-3 activity, lithium increases the stability of c-Myc in vivo and in vitro [43, 44]. c-Jun is a critical transcription factor in response to cellular stress. In neurons, c-Jun triggers apoptosis through transcriptional activation of proapoptotic genes such as Bim. GSK-3 activity can lead to elevation of c-Jun protein levels [45]. GSK-3 activity is required for c-Jun-induced death and downstream Bim expression in stressed neurons. Lithium blocks this cJun apoptotic pathway by blocking the upregulation of Bim protein in cerebellar granule neurons deprived of trophic support. This effect was mimicked by some other inhibitors of GSK-3 [46, 47]. GSK-3 promotes phosphorylation and activates the transcriptional activity of p53, a protein generally capable of orchestrating apoptosis [48]. GSK-3 interacts with p53 in both the nucleus and mitochondria to promote its proapoptotic actions at both sites [49]. Lithium treatment downregulates p53 [50]. Lithium-mediated neuroprotection against colchicine was deemed to be independent of any direct action on GSK-3; instead, lithium appeared to block the induction of cdk5 and breakdown of cdk5/p35 to cdk5/p25 evoked by colchicine [51]. Nontranscriptional events may also contribute to the proapoptotic actions of GSK-3. Bax, Bcl-2, and Bcl-X are among proteins that regulate the apoptotic triggers resulting from the mitochondrial permeability transition. GSK-3 phosphorylates Bax on Ser163 and thus stimulates the “intrinsic” death pathway by eliciting cytochrome c release from mitochondria; constitutively active GSK-3 promotes the localization of Bax to mitochondria and induces apoptosis in both transfected HEK293 cells and cerebellar granule neurons [52]. A coordinate modulation of Bax and Bcl-2 by lithium may be involved in its survival-promoting actions; lithium was shown to suppress expression of Bax while upregulating the anti-apoptotic protein Bcl-2 [50]. Lithium also increased Bcl-2 levels in frontal cortex of rats [53]. There are also experiments that link anti-apoptosis effects of lithium to rapid changes in the level of intracellular calcium concentrations. Chronic lithium treatment modifies processes

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that impact intracellular calcium signaling and homeostasis, as was noted in B-lymphoblast cells from both healthy and bipolar people [54]. Downstream effects of this modulation could possibly regulate excitotoxicity or apoptotic cell death (for review see [55]). Indeed, an elegant in vitro study with cultured cortical neurons found an acute, lithium-associated increase in intracellular calcium that inhibited apoptosis [56]. The ability of lithium to evoke changes both in transcription and in quicker biochemical events may explain the differing effects of lithium applied acutely or chronically. It has been reported that long-term but not short-term lithium pretreatment protects neurons against apoptosis [57]. There are many similar reports that presume the delayed effects are mediated by slow changes in macromolecular synthesis. In a recent study on cultured human T/C28a cells, a microarray approach revealed that genes differentially affected by lithium are involved in cellular functions such as signaling, cell cycle control and growth, cell-cell interaction, solute transport and transcription control [58]. Chronic treatment with lithium upregulated the expression of the potent neuroprotectant BDNF in rat brain [59] and in cultured neurons. BDNF neutralizing antibody suppressed the neuroprotective effect of lithium, suggesting that survival of neurons by lithium is dependent on the subsequent expression of a neurotrophin. So lithium could also promote survival of neurons indirectly through elevating the levels of neurotrophic factors [60]. BDNF increases and decreases the expression of Bcl-2 and Bax proteins respectively [61], similar to the functions achieved by lithium itself, raising the possibility that lithium can compensate for a deficiency in neurotrophins. Interestingly, the active role that lithium takes in promoting an anti-apoptotic cellular program means that its effects are not limited to preventing the passive cell death of trophic factor withdrawal; lithium can also protect neurons against active neurotoxins. The inhibition of GSK-3 permits lithium to block the activation of caspase-3 in cultured human neuroblastoma SH-SY5Y cells exposed to apoptotic stimuli [62]. Lithium prevents death stimulated by C2-ceramide [63], anticonvulsants [64], aluminum [65], ischemia [66, 67], oxidative stress [68], and endoplasmic reticulum stress [69]. These functions of lithium have been attributed to its inhibitory effect on GSK-3 because other small-molecule inhibitors of this key enzyme prevent apoptosis of neurons [70]. It is particularly noteworthy that inhibition of GSK-3 in CNS neurons also protects them against excitotoxicity [71], a phenomenon that becomes a final common mediator of neuronal death in a wide variety of conditions, including ischemia. Inhibition of ischemic neural lesions by lithium has been demonstrated. In a rat model of ischemia, chronic lithium treatment markedly reduced brain infarction and neurological deficits induced by permanent middle cerebral artery occlusion [66]. This protection could be ascribed to a blockade of apoptosis because inhibition of caspase-3 activation was evident [72]. Lithium can substantially inhibit ischemiainduced neuronal injury even if administered after the insult. Certain heat-shock proteins contribute to an endogenous compensatory response that permits survival of a fraction of the neurons subjected to ischemia; lithium has been shown to enhance the levels of both HSP70 and the activity of its acti-


vating transcription factor HSF1 [67]. The relevant target for lithium in this context could be GSK-3 because the kinase was activated in degenerating cortical neurons after ischemia [32]. Furthermore, GSK-3 can negatively regulate both DNA-binding and transcriptional activities of HSF1 [41], providing compelling evidence that GSK-3 is involved in ischemic lesions. The neuroprotective actions of lithium have begun to be tested for their more specific application to well-known neurodegenerative human disorders like Alzheimer's disease, Parkinson's disease, Huntington's dementia, and prion diseases. Lithium showed neuroprotective effects against neurotoxicity induced by MPTP (N-methyl-4-phenyl-1,2,3,6tetrahydropyridine) in an animal model of Parkinson's disease. In this disease model lithium increased the level of Bcl2 and reduced the level of Bax proteins [73]. There is another report that asserts lithium’s inhibition of GSK-3 prevents neurotoxicity after 6-hydroxydopamine lesioning, another PD model [74]. Through its effects on GSK-3, lithium can also sustain dopamine-dependent behaviors, indicating that lithium could also be considered as a candidate for mediation in dopaminergic disorders like Parkinson's disease, schizophrenia, attention-deficit hyperactivity disorder, Tourette’s syndrome, addiction, and affective disorders [75]. In an in vivo model of Huntington's disease (quinolinic acid administration), lithium diminished neuronal loss, indices of DNA damage, and activated caspase-3; these events coincided with an increase in Bcl-2 and the number of proliferating progenitor cells [76]. Lithium has been proposed as a good candidate for treatment of Huntington's disease due to its ability to elevate levels of heat-shock factor-1 [77]. There are examples of lithium acting to facilitate apoptosis [78-80], but these are largely in tumor cell models or immature cell populations, which may be of little concern in most neurodegenerative conditions. Besides playing a role in regulating cell survival, GSK3 also regulates cell proliferation. Relevant findings include an in vitro study that showed inhibition of GSK-3 after stimulation of proliferation of cerebellar granule neuronal precursors by IGF-I [81]. Lithium modulates the activity of the cell-cycle regulator cyclin D1. Lithium treatment has been shown to increase the nuclear level of cyclin D1 in SHSY5Y human neuroblastoma cells [31], increase its expression in renal epithelial cells and [14] suppress its downregulation in breast cancer cells [82]. Lithium also prevents cyclin D1 degradation in MG63 cells [83]. LITHIUM EFFECTS ON PATHOGENIC PATHWAYS OF ALZHEIMER’S DISEASE The two major elements of AD pathology are accumulation of amyloid -peptide (A) and the aggregation of hyperphosphorylated forms of the microtubule-binding protein Tau. While the precise role of A in the disease’s ultimate dementia or other aspects of its pathology—including Tau pathology—is debated, a common thread throughout the sine qua non of AD is GSK-3 [84]. The main forms of A are 40- or 42-amino acid peptides derived from proteolytic cleavage of a ~110-kD precursor protein (APP). Two enzymes perform this cleavage: secretase (BACE), which generates the aminoterminus of

Aghdam & Barger

A, and -secretase, which generates one of two major carboxytermini. The -secretase comprises at least four gene products: presenilin-1 (PS1), nicastrin, Aph-1 and Pen-2. Thus, familial forms of AD (FAD) can be inherited with very high penetrance after mutations in APP or PS1 (or PS2, thought to function redundantly or similarly to PS1). The longer form of A (A1-42) appears to play a more significant role in AD pathogenesis, as disease-causing mutations in either PS or near the -secretase site of APP increase the proportional production of A1-42. And while some cases of AD may arise from inadequate removal of A, the familial cases clearly involve overproduction of A1-42. Such overproduction is the modus operandi in most of the AD transgenic models, generally created by transgenesis of a form of the human APP gene mutated near the BACE cleavage site (“Swedish” mutation) or near the -secretase site (“London” or “Indiana” mutations) or both. Therapeutic concentrations of lithium have been reported to suppress the production of A in cultured cells and in the brains of mice expressing the Swedish mutant of APP, and this appears to reflect an impact on GSK-3 because more specific inhibition of GSK-3 enhanced A production [85]. This complexity may explain the fact that other investigators found increased A production after treatment with lithium itself, apparently resulting from an enhancement of secretase activity [86]. This is consistent with the demonstration that lithium inhibits aspects of A production that are downstream of -secretase [87]. At odds with these interpretations are data from Su et al. [88], implicating the isoform of GSK-3 in A production and documenting an inhibitory effect of lithium on A accumulation in vivo in the absence the Swedish mutation. However, it should be recognized that accumulation of A in vivo is complicated by many events beyond A production. So, the possibility remains that lithium has no net effect on cleavage of wildtype APP but enhances clearance of the peptide from the brain. And regardless of the complexity of lithium’s influence, the data have indicated potential roles for GSK-3 or - in A accumulation. Mechanistically, it is possible that the influence of GSK-3— and hence, lithium—on A production involves PS1. FADrelated mutations in PS1 correlate with increased production of A1-42 [89] and neuronal cell death [90]. PS1 interacts directly with critical components of the Wnt pathway, namely, GSK-3 and its substrate -catenin [91]. PS1 has been shown to influence the stability and transcriptional activity of -catenin, but the net effect has been controversial. Zhang et al. [92] found that wildtype PS1 stabilized catenin but FAD-mutant PS1 did not. Other investigators have reported just the opposite: destabilization of -catenin by wildtype PS1 but not FAD-mutant PS1 [93, 94]. Some of this discrepancy may arise from different backgrounds of Wnt signaling [94] or E-cadherin levels [95]. There is also conflicting data with regard to the role for GSK-3 in the effects of PS1 on -catenin (c.f. [94] and [96] versus [97] and [90]). However, expression of wildtype PS1 has been reported to cause phosphorylation and inactivation of GSK3, inhibiting apoptosis [97]. In that study, PS1 bearing a FAD mutation was associated with diminished PI3K/Akt, enhanced GSK-3 activity, and apoptosis; expression of a constitutively active Akt rescued neurons from mutant PS1-



observations [107]. Pei et al. [108] found active GSK-3 to be prominent in pre-tangle neurons, dystrophic neurites, and neurofibrillary tangles of AD brain. Ishizawa and colleagues [33] reported similar findings with the exclusion of pretangle neurons. This accumulation was interpreted to be due to redistribution rather than increased expression or activation. GSK-3 is also associated with granulovacuolar degeneration in AD [34]. GSK-3 has been shown to be closelyassociated with the phospho-tau of tangle-bearing neurons [109]. Accumulation of active GSK-3/ was observed in neurons containing NFTs but not in normal neurons or neurons with pretangles. Experimental activation of GSK-3 in brain slice cultures was subsequently shown to induce tau phosphorylation at sites recognized by antibodies “PHF-1” (Ser396/Ser404) and “Tau-1” (Ser199/Ser202) (Table 1), sites also hyperphosphorylated in AD brains [110]. In that study, inhibiting PI3K and protein kinase C (PKC) also increased tau hyperphosphorylation, suggesting that a PKC/PI3K pathway negatively regulates tau hyperphosphorylation through suppression of GSK-3 activity. Other kinases may also alter the ability of tau to serve as a substrate for GSK-3 through their own phosphorylation of tau [111].

induced neuronal cell death. Nevertheless, some data indicate that the influence of GSK-3 on APP processing is independent of alterations in the -secretase complex itself [85]. Evidence suggests that GSK-3 might influence access of APP to -secretase via effects on the Golgi apparatus [35, 98] or molecular motors like kinesin [99]. Phosphorylation of APP by GSK-3 [100] might also accelerate its processing by -secretase [101]. Wildtype PS1 also interferes with activity of the c-Jun transcription factor and thereby suppresses Jun-mediated apoptosis. PS1 suppresses the binding of Jun homodimer to the 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element (TRE) in the promoter of several genes. PS1 inhibits Jun-associated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas this suppression of apoptosis is attenuated by mutations in PS1 [102]. Like normal PS1, lithium blocks the canonical Jun-dependent apoptotic pathway [46]. But unlike PS1, lithium seems to work by blocking events downstream of Jun induction. Lithium, Its Targets, and Neurofibrillary Pathology While these connections to A production are intriguing, tau pathology is the arena where GSK-3 and lithium have been most extensively linked to AD. Tau is a microtubuleassociated protein with high expression in neurons and is most abundantly found in axons, but glial cells show tau only in pathologies distinct from AD [103]. There are many phosphorylation sites in tau, but phosphorylation at a specific subset of these sites interferes with the ability of the protein to bind and stabilize microtubules [104]. Hyperphosphorylation of these sites is also generally correlated with the presence of paired helical filaments (PHF), a tau aggregate that forms the neurofibrillary tangle (NFT) lesions required for the neuropathological diagnosis of AD. Tau protein plays a crucial role in the process of neurodegeneration. Taudepleted hippocampal neurons do not degenerate in the presence of fibrillar A, and rodent neurons expressing human tau degenerate in the presence of fibrillar A [105].

Direct in vitro interaction between GSK-3 and tau protein has been demonstrated. Under physiological conditions, tau protein binds directly and preferentially to GSK-3 rather than GSK-3 [112]. GSK-3 is one of the major kinases capable of producing the abnormal and increased tau phosphorylation that defines AD-specific sites [106, 113115]. This enzyme generates many phosphorylated sites on tau, and the evolution of GSK-3 developmental compartmentalization in neurons appears to have paralleled that of phosphorylated tau [116]. The interaction of GSK-3 with tau is also relevant to mutations in PS1 (above). Tau and GSK-3 bind directly to a common region on PS1, so it has been suggested that PS1 may regulate the kinase activity of GSK-3 on tau. A PS1 FAD mutant binds vigorously to GSK-3 and increases its phosphorylation activity on tau protein [117]. In addition, loss of presenilins promotes tau phosphorylation [118].

One of the first implications of an influence of GSK-3 on tau phosphorylation came from analysis of mice transgenic for GSK-3 [106]. Additional evidence for the involvement of GSK-3 in PHF-tau formation comes from a set of in situ Table 1.

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The hypothesized role of GSK-3 in tau pathology is further evinced by the effects of lithium, which also hint at therapeutic opportunities. Reduced tau phosphorylation both

Tau Phosphorylation Sites Relevant to AD Antibody

Epitope (P=phosph., u=unphosph.)

Immunoreactivity in AD

Influence of GSK-3

Refs.

AT8

P-Ser202 / P-Thr205

[106]

PHF-1

P-Ser396 / P-Ser404

[110, 113]

Tau-1

u-Ser199 / u-Ser202

[110, 111, 113]

205

P-Thr205

[114]

396

Tau[pS ]

P-Ser396

[114]

TG3

P-Thr231 / P-Ser235

[115]

Tau[pT ]

The conventional names of antibodies often used to analyze Tau phosphorylation are listed, along with the amino acids that create an antigenic site when phosphorylated (“P-”) or unphosphorylated (“u-”), and their characteristic binding changes accompanying AD or GSK-3 activation. References documenting the latter are also provided.


in vivo and in cultured neurons after exposure to lithium has been observed. Lithium also blocks the AD-like, prolinedirected hyperphosphorylation of tau protein [115, 119, 120]. In transgenic mice overexpressing mutant human tau, lithium treatment reduces axonal degeneration and the amount of hyperphosphorylated tau [16]. In cultured human NTera2(N) neurons, lithium reduces tau phosphorylation, increases tau binding to microtubules, and promotes microtubule assembly; these effects involve the inhibition of GSK-3 [121]. Such stabilization of microtubules could be a key factor in neuronal survival. Lithium also contributes to data implicating a broader role for events related to GSK-3 in AD pathogenic events. In rat hippocampal neurons, A (25-35 fragment) was shown to cause inhibition of PI3K, resulting in the activation of GSK3, phosphorylation of tau, and neuronal death [122]. These findings suggest that PI3K plays a critical role in regulating neuronal responses relevant to AD. Components of the Wnt pathway interfere with A neurotoxicity, an outcome also produced by lithium; these neuroprotective actions appeared

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to involve the restoration of cytosolic -catenin to control levels [123]. Inhibition of GSK-3 leads to activation of Wnt pathway and ensuing nuclear translocation of -catenin, which is required for this instance of cytoprotection [124]. Elevated expression of the anti-apoptotic protein Bcl-2 may be involved in these events [125, 126]. Another study showed that carboxyterminal fragments of APP exert neurotoxicity by inducing the expression of GSK-3 [127]. Together, these findings obviate a role for GSK-3 in neuronal deficits induced by AD-related pathogenic molecules. Theoretical interactions of GSK-3 with amyloidogenic and neurofibrillary pathogenesis and modulation by lithium are summarized in Fig. 2. Roles for Lithium in Other AD-Related Events GSK-3 could conceivably play a substantial role in mediating inflammatory responses. This would be critically important for the normal brain functioning because many disturbances in brain homeostasis can lead to inflammation with critical consequences [128]. NFB is a transcription

Fig. (2). Lithium modulation of GSK-3 events relevant to Alzheimer’s disease. GSK-3 activity can phosphorylate Tau at AD-relevant sites, perhaps reducing its association with microtubules so that it self-aggregates. GSK-3 may also facilitate the production of A. Though the mechanism is unclear, it is possible that GSK-3 interferes with vesicular transport of APP through the secretory or fast-axonal transport pathways, perhaps by phosphorylation of kinesin. This would stagnate more APP in the endoplasmic reticulum where it would be vulnerable to processing by - and -secretases. Evidence suggests that GSK-3 also interacts more directly with PS1, and wildtype PS1 may exert a homeostatic influence by activating PI3K/Akt to squelch GSK-3; FAD-mutant PS1 is reportedly deficient in this regard. Lithium directly blocks GSK-3, perhaps restoring balance to this system.



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factor associated mostly with inflammatory responses [129, 130] and appears to be regulated by GSK-3 at the level of the transcriptional complex in the nucleus [131]. These findings indicate that inactivation of GSK-3 by lithium or other specific inhibitors could serve as a tool to reduce inflammatory responses evident in AD. In one study lithium chloride reduced IL-8 production associated with NFB activity [132], strengthening the link between GSK-3 and NFB. PI3K-Akt activation and subsequent inhibitory phosphorylation of GSK-3 seems to act beneficially in the antiinflammatory regulation of renal tubular epithelial cells. In these cells, specific inhibition of GSK-3 activity by lithium suppressed the ability of tumor necrosis factor to induce an inflammation-related chemokine [133]. Besides serving as a survival signal, activated Akt serves an indirect antiinflammatory role by preventing the exposure of phosphatidylserine on the external leaflet of neuronal membranes [134], an event that can trigger activation of nearby microglia. Once activated, microglial cells release aggravating mediators like nitric oxide (NO), interleukin-1 (IL-1), and amino acid excitotoxins that will further harm adjacent neurons [135].

heimer’s disease without the unintended negative consequences of lithium.

Sustained proliferation and concomitant differentiation of neural stem cells resident in the adult brain could be favorable for prevention of or recovery from neurodegeneration in conditions like Alzheimer’s disease. There are now hints that lithium or other inhibitors of GSK-3 could even facilitate this aspect of regeneration. GSK-3 plays prominent roles in differentiation of embryonic stem cells (ESCs) and hippocampal neuroprogenitor cells. Inactivation of GSK-3 maintains an undifferentiated phenotype in ESCs [136]. However, lithium was still able to increase neuronal differentiation of neuronal progenitor cells [137], and inhibition of GSK-3 by lithium led to increased neurogenesis in the dentate gyrus of the rodent hippocampus [138]. Lithium also significantly suppresses the apoptotic death of neural stem cells [139], which can replenish both neurons and glial cells to repair damage within the adult brain.

ACKNOWLEDGEMENTS The authors appreciate Drs. Peter S. Klein (U. Pennsylvania) and James R. Woodgett (U. Toronto) for insightful discussions. Dr. Barger is supported by funds from the United States National Institutes of Health: P01AG12411, R0146439, and R01AG17498. ABBREVIATIONS A

=

Amyloid -peptide

AD

=

Alzheimer's disease

APC

=

adenomatous polyposis coli

BACE =

-Secretase

APP

=

-Amyloid precursor protein

BIO

=

(2'Z,3'E)-6-bromoindirubin-3'-oxime

dsh

=

Dishevelled

ESCs

=

Embryonic stem cells

FAD

=

Familial AD

GSK-3 =

Glycogen synthase kinase-3

IL-1

Interleukin-1

=

IMPase =

Inositol monophosphatase

MPTP

=

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NFT

=

Neurofibrillary tangle

NO

=

Nitric oxide

PHF

=

Paired helical filaments

PI3K

=

Phosphatidylinositide 3'-OH kinase

PKC

=

Protein kinase C

PS1

=

Presenilin-1

CONCLUSIONS

Tcf/Lef =

T-cell factor/lymphoid-enhancer factor

The arguments outlined above have led to speculations that lithium could promote several desirable outcomes in Alzheimer’s disease, including prevention of tau phosphorylation, inhibition of A secretion, regeneration to replace lost neurons, as well as a more general protection of neurons against several forms of toxicity. Nevertheless, the caveats must be acknowledged. Epidemiological analysis indicates that patients who received lithium had a higher risk of diagnosis of dementia compared with those who did not (adjusted odds ratio: 1.8, 95% CI 1.1-2.8), and there was a trend toward increasing risk with increasing numbers of lithium prescriptions [140]. There is also one report indicating that lithium increases the production of A in vitro (in APPtransfected CHO cells and virally transduced neurons) [86]. However, this effect of lithium did not involve inhibition of GSK-3; in fact, another GSK-3 inhibitor appeared to suppress A production. Thus, the promising experimental effects of lithium may be of primary utility in steering drug discovery trials toward its target: GSK-3. More selective inhibition of this enzyme may have beneficial effects in Alz-

TPA

=

Tetradecanoylphorbol-13-acetate

TRE

=

TPA-responsive element

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[3] [4] [5] [6]

[7]

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Received: February 14, 2006

Revised: February 22, 2006 Accepted: March 03, 2006

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