Novel therapeutics for Alzheimer's disease: An update

Abstract

As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a signifcant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease. A considerable need exists for the development of an effective therapy to prevent, or at least delay, the progression of AD. Current hypotheses for the pathogenesis of AD are discussed in this review, with a particular emphasis on the implications of these hypotheses with respect to treatment strategies and preventive measures.

Introduction

The complex molecular interactions that are involved in the development and progression of Alzheimer's disease (AD) are only partly understood. While early-onset familial AD is linked directly to specific gene mutations, the late-onset sporadic form of the disease, which accounts for approximately 95% of all AD cases [1], likely results from the complex interplay of molecular, environmental and genetic factors. With the identification of novel mechanisms that lead to neurodegeneration, the characteristic pathologies of AD, notably the β-amyloid (Aβ)-containing senile plaques and the hyperphosphorylated tau protein aggregates that form neurofibrillary tangles (NFTs), are no longer considered to be causative but, instead, are considered to be the secondary products of prior insults [2]. Importantly, the development of NFTs may protect against neuronal damage, as mutations in the Aβ precursor protein (APP) [3–5] and the presence of NFT-containing neurons [6,7] are associated with the reduced steady-state production of Aβ [8] and with reduced levels of oxidative stress, respectively [9]. Moreover, rather than readily succumbing to neuronal death, NFT-containing neurons often survive for decades [10]. Conversely, oxidative stress and mitochondrial malfunction are two of the primary factors that are believed to be responsible for initiating the neuronal cascade that leads to AD [11,12]. Without intervention, oxidative stress and mitochondrial malfunction may elicit the production and aggregation of Aβ and tau, as well as neuroinflammation, aberrations in the cell cycle, small-vessel disease and an overall decline in cognitive function [12,13].

Notably, the aggregation of Aβ in the form of senile plaques and the formation and fibrillization of hyperphosphorylated tau into NFTs generate strong responses from the surrounding cellular environment and are responsible for much of the late-stage cognitive decline observed in patients with AD. Alternative theories for the pathogenesis of AD suggest that such pathologies are primarily responsible for neurodegeneration [14]. For example, once Aβ has aggregated sufficiently, this protein elicits (among other effects) a neuroinflammatory response via the activation of microglia and astrocytes [15,16]. Following the initial neuroinflammatory response, the neurotoxic biproducts of inflammation, such as the downstream intermediates of the kynurenine pathway (the primary route of l-tryptophan metabolism), cause additional oxidative damage to cells [17–23]. Similarly, the hyperphosphorylated tau fibrils create cytoskeletal stresses and promote neuronal dysfunction [24,25]. Therefore, the chronology and causality of the multitude of pathologies observed in AD are responsible for instilling controversy in the field, rather than the effects of such pathologies.

Three approaches for the treatment of AD are possible: (i) treatments that prevent the onset of the disease by sequestering the primary progenitors; (ii) disease-modifying treatments that target and reduce the secondary pathologies of the disease, leading to the cessation or the reversal of disease progression; and (iii) symptomatic treatments that treat the tertiary cognitive symptoms of the disease and protect from further cognitive decline. Notably, the appropriate treatment method depends on the severity of the disease in each individual; however, preventive and disease-modifying treatment strategies are the only hope for the eradication of AD from the general population.

Preventive treatments for Alzheimer's disease

The prevention of AD is the most effective strategy for eliminating the occurrence of this disease. Oxidative stress and mitochondrial abnormalities have been implicated in the initiation of AD [9,26,27]; a successful prevention regimen thus may act by attenuating these phenomena [28].

Antioxidants

Oxidative stress represents a particularly attractive target for therapeutic intervention because of the ubiquitous role that this type of stress plays in disease development. Reactive oxidative species (ROS) are generated within the mitochondria of normal respiring cells [29]: the oxidation-reduction reactions that establish the proton gradient in oxidative phosphorylation (OXPHOS)/ATP production generate free radical intermediates via the transfer of electrons. Despite the resident cellular sequestration mechanisms that antagonize the release of ROS, free radicals escape from the electron transport chain (ETC; the escape of free radicals is estimated to be approximately 10¹¹ ROS/cell/day [29]), causing damage to mitochondrial DNA (mtDNA), proteins and phospholipids. The levels of damaged mtDNA, proteins and phospholipids are increased in AD [2,11,13], suggesting that antioxidant therapies may be protective against free-radical generation and cellular oxidative damage in this disease.

Naturally occurring antioxidants represent one treatment option for AD. These compounds, including vitamin E and vitamin C, are associated with the reduced prevalence and incidence of AD [30–32] and, when used in combination, are considered to have synergistic biochemical antioxidant potential. However, vitamin E treatment alone was not effective against the progression of AD in randomized clinical trials [33].

Mitochondria are the primary source of ROS [34], and oxidative damage to mitochondrial components precedes that of any other cellular component during the development of neurodegenerative disease [13,35–37]. Two potential antioxidant drugs that are targeted to the mitochondria are under investigation for the potential treatment of AD. The first drug is coenzyme Q₁₀ (CoQ₁₀), a component of the ETC that is present in the inner mitochondrial membrane and conducts the high-energy electrons from complex I to complex II. Several studies have demonstrated that nullifying oxidative damage and attenuating mitochondrial dysfunction has neuroprotective effects [38,39]. For example, in an MC65 neuroblastoma cell model of AD, CoQ₁₀ suppressed H₂O₂ and O₂- production (the most prevalent free radicals) and provided complete protection from oxidative-induced neurotoxicity [40]. However, CoQ₁₀ has two major limitations as a therapy. First, the functioning of CoQ₁₀ is dependent entirely on the functioning of the ETC, which facilitates the redox cycling of the enzyme from ubiquinone (oxidized form) to ubiquinol (reduced form). This requirement becomes critical when oxidatively damaged mitochondria contain defective OXPHOS systems and damaged ETCs, and thus cannot recycle CoQ₁₀ appropriately. Second, although oxidative damage was attenuated following the oral administration of CoQ₁₀ to rodents, the levels of the CoQ₁₀ protein were not increased in the brain [40–42], suggesting that CoQ₁₀ is unable to cross the blood-brain barrier (BBB). Thus, CoQ₁₀ derivatives are being developed that do not require intact ETC functions and that demonstrate increased BBB permeability.

The second potential antioxidant drug is the CoQ₁₀ derivative MitoQ (Antipodean Pharmaceuticals Inc), a triphenylphosphonium-linked ubiquinone derivative [43]. MitoQ concentrates highly in the mitochondria because of the large mitochondrial membrane potential (Δψm) [44], and is also an effective antioxidant in the absence of a functioning ETC [45,46]. For example, in in vitro studies using a leukemic cell model, following the depletion of glutathione, MitoQ blocked the generation of ROS effectively, protected the mitochondrial protein redox status, preserved the structural integrity of mitochondria, and blocked cell death [45]. MitoQ is in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection [47].

Other mitochondrial antioxidants that are under investigation for the potential treatment of AD include acetyl-l-carnitine (ALCAR) and r-α-lipoic acid (LA), both of which were demonstrated to reduce oxidative stress and mitochondrial abnormalities in cellular mouse models of AD [48], and to restore cognitive functions in aged rats [49–53] and dogs [54,55]. Notably, the coadministration of ALCAR and LA reduced the level of damage to hippocampal neuronal mitochondria significantly, with the mitochondria retaining their structural integrity and the number of normal mitochondria increasing significantly in both young and old rats [52]. These results provide considerable hope for the effectiveness of future therapies that target oxidative stress and mitochondrial disruptions in AD.

Protective agents of mitochondrial dynamics

Mitochondrial integrity is vital to cellular health. Mitochondria are not static organelles, but are dynamic bodies that divide constantly and fuse within the cell in response to environmental demands [56,57]. The delicate balance of fission and fusion is highly regulated by specific mitochondrial membrane proteins and their associated complexes [12,56], and provides, among other functions, a defensive mechanism against the deleterious presence of defective mitochondria that may be the result of mutation or oxidative damage. Mitochondrial fusion permits the exchange of lipid membranes and inter-mitochondrial contents (ie, mtDNA, and OXPHOS and ETC proteins); and mitochondrial fission, coupled with mitochondrial fusion and autophagy, allows the sequestration and elimination of irreversibly damaged mitochondria [58–60]. The neurons of patients with AD demonstrate significant alterations in mitochondrial structure [61,62]. In addition, the mitochondrial distribution and levels of fission and fusion proteins are altered in hippocampal pyramidal neurons in patients with AD [63,64]. Therefore, an agent that protects the proteins that are involved in mitochondrial fission and fusion may maintain the protective balance of these proteins and may prevent the neurodegeneration observed in AD.

Notably, while preventive measures would protect the brain from the onset of AD, after significant oxidative damage and mitochondrial imbalances have occurred and the associated pathologies have accumulated within the brain, reversing the course of the disease is likely beyond the scope of agents that target oxidative damage and modulate mitochondrial dynamics. At that point in disease progression, only disease-modifying or symptomatic treatments would be of benefit to patients.

Disease-modifying treatments for Alzheimer's disease

The neuropathological cascade of AD results from the age-related accumulation of neurodegenerative initiators and mediators, such as ROS and mtDNA mutations. However, after a threshold of cellular damage has been reached, the cell enters a compensatory 'oxidative steady state' that enables a basic level of operational activity, despite the depleted levels of functioning mitochondria and other cellular components. The hallmark pathologies of AD develop during this period of steady-state oxidation, and medications targeting such secondary pathologies may inhibit further disease progression.

Anti-Aβ therapies

Interestingly, research indicates that Aβ secretion has antioxidant properties [65–71] and is a compensatory strategy that is used by the cell to antagonize uncontrolled oxidative stress [2,11,13]. In AD, Aβ secretion follows the appearance of ROS and mitochondrial anomalies [29]. However, the continuous secretion of Aβ, coupled with the continuous levels of oxidative stress that are caused by mitochondrial damage, contributes to the cascade of events that lead to neurodegeneration. In particular, Aβ can succumb to oxidative stress and develop dityrosine cross-linkages that prevent the protein from being soluble in vivo, thereby promoting Aβ aggregation [70,72]. This non-soluble, antagonistic form of Aβ and the formation of senile plaques are the primary targets for the therapeutic strategies that are being investigated for AD.

Three treatment approaches that target Aβ may provide potential benefits to patients with AD: anti-aggregation agents; secretase enzyme modulators; and Aβ-clearance mechanisms. These approaches are described in the following sections.

Anti-Aβ aggregation

The anti-aggregation agents target the fibrillization of the Aβ peptide. One anti-aggregation approach that has demonstrated significant results in vitro is that of nanoparticle-conjugated metal chelators. Chelators disrupt the interactions of Aβ with redox metals in the brain, thereby preventing aggregation. Specifically, iron and copper, the levels of which are increased in the brains of patients with AD [73,74], as well as zinc, are suggested to play an important role in Aβ self-assembly and neurotoxicity [75–78]. While metal chelators (eg, desferrioxamine, EDTA [ethylenediaminetetracetic acid] and clioquinol [iodochlorohydroxyquin] [79–81]) can attenuate the effects of Aβ [71,82–84], their use as therapeutic agents is hindered by an inability to cross the BBB. However, a recent study proposed the use of nanoparticle conjugation to deliver iron chelators effectively across the BBB, without affecting their metal-binding ability [85,86]. In this study, the Nano-N2PY nanoparticle-chelator conjugate protected neuronal cells against Aβ-associated cyctotoxicity in vitro, with no adverse effects on cell growth or proliferation. Furthermore, the conjugate prevented the formation of Aβ-aggregate completely [85]. These results have yet to be translated to animal models of neurodegeneration, but present exciting potential for the use of metal chelators as therapies for AD.

The aggregation of Aβ was also diminished significantly in transgenic (Tg) mouse models of AD following the administration of the neurohormone melatonin [87]. The long-term administration of melatonin reduced the deposition of Aβ within the hippocampus and entorhinal cortex significantly [87], presumably through the prevention of Aβ fibrillogenesis [88–90]. Although melatonin also suppressed the levels of proinflammatory cytokines (eg, TNFα) and reduced the levels of oxidative stress in the cortex, its primary mode of action was the prevention of Aβ aggregation. As aggregated Aβ itself induces inflammatory neuronal responses, as well as ROS generation and mitochondrial damage, the effects of melatonin on oxidative stress and proinflammatory cytokine levels may be the result of its suppression of Aβ aggregation. Moreover, the long-term safety of melatonin in humans is known, and this fact, when combined with the beneficial attenuation of the pathogenesis of AD, renders this agent particularly appealing.

The cyclohexanehexol stereoisomer ELND-005 (scyllo-inositol; Elan Corp plc/Transition Therapeutics Inc) is also under investigation for its anti-Aβ oligomerization properties [91]. The administration of ELND-005 to Tg mice was successful in reducing the accumulation of Aβ oligomers, and also reversed memory deficits [92]. Phase II clinical trials of the compound are ongoing, with results expected by mid-2010 (ClinicalTrials.gov identifiers: NCT00568776 and NCT00934050).

Secretase enzyme modulation

Another approach for reducing the levels of Aβ involves modulating the activity of the β- and γ-secretase cleaving enzymes to inhibit the production of Aβ. The β- and γ-secretase enzymes are aspartyl proteases that convert APP to Aβ; treatment strategies that involve the inhibition of these two enzymes aim to reduce the levels of cerebral amyloid [93,94]. Currently, several agents targeting these enzymes are being developed, including the γ-secretase inhibitors MK-0752 (Merck & Co Inc) and semagacestat (LY-450139; Eli Lilly & Co; NCT00762411 and NCT00594568) [94–96], and the β-secretase inhibitor Posiphen (QR Pharma Inc) [91,97]. Phase II clinical trials for Posiphen are ongoing [91,98], and semagacestat has progressed to phase III trials (NCT01035138).

Aβ clearance

Strategies that aim to reduce the cerebral levels of Aβ directly are of therapeutic significance; immunotherapy is one such approach that is at advanced stages of clinical testing for AD, despite the potential safety concerns of this approach [99,100]. Immunotherapies are designed to use the body's immune system to eliminate the deposition of existing Aβ senile plaques. Active immunization requires the introduction of an antigen that mimics Aβ, so that antibodies targeting the antigen are produced; these antibodies subsequently bind to Aβ to facilitate its clearance from the CNS [93,97]. The development of AN-1792 (an aggregated amyloid peptide), the first active immunotherapy for AD, was halted in January 2002 because of the occurrence of meningoencephalitis in 6% of vaccinated patients. Second–generation amyloid antigens have been designed to decrease the likelihood of T-cell activation, which was considered responsible for the adverse affects observed with AN-1792 [93]. These second-generation immunotherapies include CAD-106 (Cytos Biotechnology AG/Novartis AG) and vanutide cridificar (ACC-001; JANSSEN Alzheimer Immunotherapy/Pfizer Inc), both of which are in phase II clinical trials (eg, NCT00956410 and NCT00479557, respectively).

Alternatively, the passive immunization method involves the parenteral administration of a specific antibody or pooled non-specific antibodies, thus requiring less contribution from the patient's immune response – a major limitation in an elderly cohort. One such passive immunization approach is the humanized Aβ-targeted mAb bapineuzumab (AAB-001; JANSSEN Alzheimer Immunotherapy/Pfizer Inc), which is in phase III clinical trials in patients with AD [91]; however, treatment with this mAb has not resulted in improvements in cognitive performance tests (Alzheimer's Disease Assessment Scale Cognitive Subscale [ADAS-cog]), except in post-hoc analyses (NCT00667810, NCT00676143, NCT00575055 and NCT00574132) [101]. The phase III trial, which is expected to be completed in April 2011, will elaborate on the safety and efficacy of bapineuzumab [91]. Other passive immunization drugs that are being developed include solanezumad (LY-2062430; Eli Lilly), which has completed phase II trials (NCT00329082, NCT00749216 and NCT00749216) and is undergoing phase III trials (NCT00905372 and NCT00904683); an immunoglobulin (Baxter International) that is in phase II trials [102]; and PF-4360365 (PF-04360365; Pfizer), which is undergoing phase II trials (NCT00722046).

Cholesterol-lowering statins, such as the FDA-approved drug simvastatin [103], have been clinically unsuccessful as therapies for AD, despite demonstrating initial Aβ clearance effects [93,97]. Therefore, whether amyloid-lowering strategies ultimately will be successful in the treatment of AD is unclear [99,100].

Tau-based therapies

Another significant aspect of AD pathology that provides a potential target for therapeutic intervention is the hyperphosphorylated form of the microtubule-associated protein tau. Tau hyperphosphorylation and the presence of this protein in an aggregated form in NFTs are correlated with cognitive decline in patients with AD [8,104]. Furthermore, NFT concentrations are used as a definitive marker for the postmortem diagnosis of AD [105]. Thus, therapeutic strategies that target hyperphosphorylated tau proteins are potentially relevant for the treatment of AD.

Microtubule stabilization

During the past several years, the investigation of NFTs as a possible therapeutic target for the treatment of AD has yielded several exciting approaches. First, as the hyperphosphorylation and subsequent aggregation of tau in NFTs impairs the function of microtubules within the cell [24,25], and reduces microtubule density and fast axonal transport [106,107], an agent that stabilizes microtubules in vivo has potential therapeutic efficacy in AD. In particular, the administration of the microtubule-stabilizing drug paclitaxel to tau-Tg mice for a 3-month period resulted in significant improvements in fast axonal transport and microtubule density [108]. Motor function was also improved in paclitaxel-treated mice [108]. Importantly, however, paclitaxel does not cross the BBB readily [109,110], and must therefore reach the brain indirectly via a peripheral uptake and retrograde transport mechanism, a requirement that reduces the efficacy of this drug considerably [111]. The limited ability of paclitaxel to cross the BBB presents a significant challenge because the high doses required for this drug to enter the brain elicit a potent antimitotic element [111] and other adverse side effects [112]. Fortunately, the octapeptide NAPVSIPQ, termed NAP based on the amino acid sequence, can cross the BBB and was demonstrated to reduce tau phosphorylation in tau-Tg mice, presumably via the stabilization of microtubules [109,113,114]; the effect of NAP provides support for the possibility of an effective microtubule-stabilizing drug for the treatment of AD.

Inhibition of hyperphosphorylation

The attenuation of NFT formation may also be achieved via the inhibition of tau hyperphosphorylation. Specifically, the phosphorylation of the tau protein at Ser²⁶², Ser²³⁵ and Thr²³¹ was demonstrated to enhance tau fibrillization and aggregation at the expense of the microtubules with which the protein associates [115–118]. Therefore, methods aimed at preventing the phosphorylation of specific sites in the tau protein may elicit beneficial results, particularly if the effect of the inhibitor were sufficiently selective. In this regard, glycogen synthase kinase 3 (GSK3), an enzyme that is responsible for the regulation of various cell processes [119], was demonstrated to colocalize with NFTs in the brains of patients with AD [120]. In addition, the overexpression of GSK3 in Tg mice resulted in increased tau hyperphosphorylation and behavioral deficits [121,122]. Significantly, the administration of lithium chloride (an inhibitor of GSK3) to tau-Tg mice reduced the levels of both tau phosphorylation and insoluble tau [123,124]. In addition, the treatment of presymptomatic animals with lithium chloride prevented the onset of tau pathology and reduced existing pathologies in mice with NFTs, although the presence of NFTs persisted following treatment [125]. Similarly, in rodent models, other small-molecule tau-kinase inhibitors were demonstrated to reduce tau hyperphosphorylation, including the non-specific kinase inhibitor SRN-003–556 and the GSK3 inhibitors CHIR-98014 and SB-216763 [126].

The tau protein may also be modified post-translationally at certain serine and threonine residues via the addition of β-N-acetylglucosamine (O-GlcNAc), in a manner that is reciprocal to tau phosphorylation and thus to fibrillar formation. Consequently, increased levels of tau O-linked glycosylation correspond directly to decreased levels of tau phosphorylation [127,128]. Therefore, the modulation of the O-GlcNAc-cleaving enzyme O-GlcNAcase has the potential to prevent tau hyperphosphorylation. Consistent with this hypothesis, the acute administration of the O-GlcNAcase inhibitor thiamet-G to normal rats reduced the phosphorylation of tau at the Ser³⁹⁶, Ser⁴⁰⁴ and Thr²³¹ residues [127], thereby demonstrating the mechanistic importance of O-GlcNAcase in tau phosphorylation.

Inhibition of oligomerization/fibrillization

Another method of disrupting NFTs involves the direct inhibition of tau oligomers and of fibril assembly that prevents the formation of toxic species and increases the levels of monomeric tau, leading to the effective stabilization of cellular microtubules [111,129]. The histological dye methylene blue (Rember; TauRx Therapeutics Pte Ltd) was reported to inhibit tau interactions and to alter the structure of the paired helical filaments of tau in brains from patients with AD. Phase II clinical trials of methylene blue have been completed with therapeutically positive data, and phase III trials are planned [97,130]. Similar inhibitors of tau-fibril assembly have been identified and are being investigated, but none has reached the clinical stages of development [131–133].

Enhancement of tau degradation

The disruptive effects of aggregated, hyperphosphorylated tau can also be eliminated by the upregulation of the intracellular degradation of the protein through the ubiquitin proteosome system or through macroautophagy [111]. In the ubiquitin proteosome degradation pathway, a targeted protein is tagged with ubiquitin and subsequently recognized and degraded by the proteosome complex [134]. As the ubiquitin proteosome system requires that the target protein is threaded through the narrow opening of the proteosome, the activation of this system degrades only the non-fibrillar phosphorylated tau. Nevertheless, the Hsp90 inhibitor mediated degradation of the smaller non-fibrillar phosphorylated tau. Because Hsp90 is primarily responsible for the ATP-driven refolding of denatured proteins, the inhibition of this protein halts the attempted preservation of phosphorylated tau by this chaperone effectively, thereby enhancing tau degradation [135–137]. For example, the Hsp90 inhibitor EC-102, which was administered to human tau-expressing Tg mice for 7 days, reduced the levels of hyperphosphorylated tau in the brain [135,138]. Moreover, EC-102 inhibited the formation of Hsp90/non-fibrillar phosphorylated tau complexes in cortical homogenates from the brains of patients with AD effectively, at a concentration that was 1000-fold lower than for control homogenates [135]; thus, clinically safe doses of EC-102 are a possibility.

Large tau oligomers and fibrils are degraded through macroautophagy, a mechanism that can be induced by the drug sirolimus (rapamycin). Treatment with sirolimus reduced both the cellular levels of insoluble tau and the associated toxicity in Drosophila expressing wild-type or mutant forms of tau [139]. Unfortunately, because of the unintentional effects of sirolimus on mTOR signaling networks, this drug is not considered safe for the treatment of AD, despite the benefits yielded with treatment of tau-mutated Drosophila [140]. In addition, the use of sirolimus as an anti-tau agent in patients with AD is further restricted because this compound induces immunosuppression [111]. However, the inhibition of an mTOR-independent target (ie, inositol monophosphatase) by treatment with lithium chloride caused the upregulation of autophagy and beneficial changes in the levels of aggregated tau (in addition to the inhibition of GSK3, as described in the Inhibition of hyperphosphorylation section) [111]. Therefore, although much has yet to be elucidated with respect to the modulation of macroautophagy, the targeting of this process for the treatment of AD remains a possibility.

Attenuating the permeability of the mitochondrial permeability transition pore

Although Aβ-senile plaques and hyperphosphorylated tau aggregates are the most studied facets of AD, other pathological phenomena associated with this disease merit analysis. The mitochondrial permeability transition pore (mPTP) is a transmembrane protein complex that regulates the permeability of the inner mitochondrial membrane that is necessary for competent ETC function and ATP synthesis. Notably, in AD, mPTP breach occurs because of Aβ-induced stress [141], eliciting a collapse in the mitochondrial membrane potential (Δϕm) and amplifying the apoptotic mechanisms by the release of apoptogenic proteins from the inner-membrane space [142–144]. The antihistamine drug latrepirdine (Dimebon; Medivation Inc/Pfizer Inc) is an agent that has been demonstrated to block the opening of the mPTP effectively, and to protect against Aβ-induced cellular dysfunction and death [145–148]. In two trials in patients with mild-to-moderate AD, latrepirdine resulted in significant improvement in cognition (Mini Mental State Examination [MMSE] and ADAS-cog), function (Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory [ADCS-ADL]) and behavior (Neuropsychiatric Inventory) scores [145,149]. Moreover, few adverse side effects were observed in both trials, thereby confirming the safety of latrepirdine [145,149]; the use of latrepirdine in Russia as an antihistamine for more than two decades is a further testament to the safety of this agent. The results of the latrepirdine phase III trial, which are expected in early 2010, are anticipated with interest.

Inhibiting glutamate-mediated excitotoxicity

Glutamate-mediated excitotoxicity is thought to contribute to the selective neurodegeneration observed in AD [93]. The inhibition of glutamate-mediated excitotoxicity has provided some therapeutic benefits in patients with mild-to-moderate AD. In particular, the NMDA receptor antagonist memantine is the only treatment available for AD that targets neurodegeneration [93,150]. Glutamate-mediated excitotoxicity is thought to be the result of the overactivation of the NMDA glutamate receptors, caused by an impaired uptake of excitatory amino acids [93]. Consequently, an interruption to this excitotoxic pathway prevents cells from succumbing to excitotoxic death, while enabling normal cognitive activation and memory formation. Recent studies have implicated memantine in the prevention of APP and tau expression via the inhibition of a translation initiation mechanism that is mediated by the internal ribosome entry site [150]. While the actions of memantine are beneficial, regardless of its mechanism of action, the overall effectiveness of this agent in delaying the progression of AD is modest [15,151,152].

Reducing luteinizing hormone concentrations

Considerable evidence exists for the role of an altered hormonal balance in patients with AD, suggesting that treatments that attenuate the altered hormonal homeostasis in an individual with the disease may be beneficial. Women have an approximately 2-fold increased risk of developing AD compared with men [153]. The increased incidence of AD in women has been attributed to menopause or age-related changes in the hypothalamic-pituitary-gonadal axis hormone levels, such as declines in sex steroids [154]. In Down's syndrome (DS), in which affected patients develop AD at a relatively early age [155], the gonadotropin luteinizing hormone (LH) is considered to have a role in the development of AD. Specifically, men with DS have an increased prevalence of AD, and hormonal investigations indicate that men with DS have higher levels of circulating LH compared with women with DS, while the reverse is true in healthy individuals [156]. Moreover, LH is the only hormonal factor that explains the gender predisposition for AD in both the healthy population and in those individuals with DS. Consequently, studies on LH and LH-based therapies have yielded exciting and promising results.

Individuals with AD have a 2-fold increase in serum LH concentrations, as compared with age-matched controls [157,158], and also have increased levels of LH in the hippocampus [155,156,159]. Furthermore, LH was demonstrated to drive APP toward the amyloidogenic pathway in vitro [160]. The gonadotropin-releasing hormone (GnRH) analog and agonist leuprolide acetate specifically reduces LH concentrations through the downregulation of GnRH receptors in the anterior pituitary [93]. In APP-mutant Tg mice (Tg2576) [156,160] and humans, the agent was demonstrated to reduce Aβ deposition [156] and to modulate cognitive performance, respectively (NCT00076440). Phase II clinical trials with leuprolide acetate indicated that high doses of the agent stabilized cognitive decline (as assessed by ADAS-Cog and ADCS-CGIC [ADCS Clinical Global Impression of Change] scores) and daily living activities (as assessed by the ADCS-ADL scale) (NCT00063310).

Symptomatic treatments for Alzheimer's disease

As researchers continue to investigate drugs that may prevent or reverse AD, the current burden of this disease on society demands some form of treatment strategy for the individuals affected. Although current treatments do not provide a long-term reduction of AD pathology or the reversal of disease progression, these therapies nonetheless postpone the inevitable decline in cognition by attenuating the epiphenomena of AD. Currently, the most widely used of these symptomatic treatments are cholinesterase inhibitors.

Cholinesterase inhibitors inhibit the enzymatic degradation of the neurotransmitter ACh by blocking the activity of AChE [161,162]. Because cholinergic neurotransmission is lacking in patients with AD, most notably in the basal forebrain [163], an increase in the synaptic levels of ACh enhances cognitive function [93]. Specifically, 50% of patients that undergo AChE inhibitor therapy report cognitive stability for 1 year; in addition, the beneficial effects of AChE inhibitor therapy can be maintained for up to 36 months [164–166]. However, although AChE inhibitor therapy is beneficial, a pathological reversal of, or cure for, AD is not achieved, and these treatments therefore represent only a short-term therapeutic approach. The positive impact on cognition, however, is apparent, and is clinically valuable.

Conclusion

As outlined in this review, much progress has been made in the search for an effective treatment for AD. Agents that potentially prevent or delay the progression of AD are being assessed in preclinical studies and clinical trials. Preventive measures (eg, antioxidants, mitochondrial antioxidants and mitochondrial dynamics protectors) will benefit an individual only prior to the onset of clinical dementia. After clinical dementia has been reached, the direct methods of preserving neuronal operational integrity will not fully impede the cascade of oxidative stress, mitochondrial decay, Aβ secretions, NFT accumulation and tau hyperphosphorylation. Disease-modifying remedies have been designed to treat mild-to-moderate AD. The development of drugs that are able to reduce and clear Aβ, to stabilize the tau and microtubule proteins, to protect the mitochondrial membrane potential and to prevent excitotoxicity ideally will halt the cascade that leads to the development of AD. With the development of such drugs, the attenuation of AD epiphenomena will not be required, as the disease will be treated successfully. Ultimately, although the majority of therapeutics will require a long process of clinical development, the overall successes described in this review indicate that an effective prevention treatment or cure for AD is possible.

Abbreviations

Aβ

β-Amyloid

APP

Aβ precursor protein

AD

Alzheimer's disease

ADAS-cog

Alzheimer's Disease Assessment Scale Cognitive Subscale

ADCS-ADL

Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory

BBB

blood-brain barrier

ETC

electron transport chain

NFT

neurofibrillary tangle

mtDNA

mitochondrial DNA

OXPHOS

oxidative phosphorylation

ROS

reactive oxidative species

Tg

transgenic