Emerging therapeutics for Alzheimer's disease.

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ANNUAL REVIEWS

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Further

Annu. Rev. Pharmacol. Toxicol. 2014.54:381-405. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/27/14. For personal use only.

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Emerging Therapeutics for Alzheimer’s Disease Karen Chiang and Edward H. Koo Department of Neurosciences, University of California, San Diego, La Jolla, California 92093; email: [email protected], [email protected]

Annu. Rev. Pharmacol. Toxicol. 2014. 54:381–405

Keywords

The Annual Review of Pharmacology and Toxicology is online at pharmtox.annualreviews.org

Alzheimer’s disease, amyloid-β, tau, therapeutics, drug development

This article’s doi: 10.1146/annurev-pharmtox-011613-135932

Abstract

c 2014 by Annual Reviews. Copyright All rights reserved

Despite decades of intense research, therapeutics for Alzheimer’s disease (AD) are still limited to symptomatic treatments that possess only short-term efficacy. Recently, several large-scale Phase III trials targeting amyloid-β production or clearance have failed to show efficacy, leading to a reexamination of the amyloid hypothesis as well as highlighting the need to explore alternatives in both clinical testing strategies and drug discovery targets. In this review, we discuss therapeutics currently being tested in clinical trials and up-and-coming interventions that have shown promise in animal models, devoting attention to the mechanisms that may underlie their ability to influence disease progression and placing particular emphasis on tau therapeutics.

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INTRODUCTION


An unwanted result of the aging populations around the globe is the development in older individuals of progressive loss of memory and brain atrophy, which characterize Alzheimer’s disease (AD) and other age-associated dementing disorders. AD is an especially devastating disease, both emotionally and economically, for the patient, their caregivers, and society at large (1). The two primary pathological hallmarks are (a) amyloid plaques, composed of amyloid-β (Aβ), a cleavage peptide derived from amyloid precursor protein (APP), and (b) neurofibrillary tangles (NFTs), primarily composed of hyperphosphorylated tau protein. Although the relationship among plaques, tangles, and the pathophysiology of AD is still less than clear, much evidence supports a significant contribution of Aβ and tau oligomers to disease progression. In this review, we primarily discuss amyloid and tau therapeutics with a lengthier discussion of tau, as amyloid-centric interventions have previously been covered in many recent excellent reviews.

THE AMYLOID CASCADE HYPOTHESIS According to the influential amyloid cascade hypothesis, the accumulation and subsequent deposition of Aβ in the brain is the initiating event of a thus far irreversible progression that culminates in AD (2, 3). The upstream role of Aβ versus tau was initially proposed in response to several lines of genetic evidence: the localization of APP to chromosome 21, which linked the consistent manifestation of AD in older Down syndrome patients to their duplication of this chromosome, and the discovery of APP gene mutations in families with a history of early-onset AD. All familial Alzheimer’s disease (FAD) mutations discovered to date affect the processing or aggregation propensity of Aβ (4), and the genetic evidence in combination with experimental work on APP strongly bolsters the hypothesis that abnormal Aβ production or accumulation is a cause of both FAD and sporadic AD and has fueled the furious development of numerous antiamyloid therapeutics. Cleavage of APP proceeds either via the nonamyloidogenic or the amyloidogenic pathway; only the latter results in the production of full-length Aβ peptides. Amyloidogenic processing involves sequential cleavage first by β-secretase [β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)] and then by γ-secretase, a multiprotein complex in which presenilins act as core catalytic subunits, resulting in the release of Aβ into the extracellular compartment (4). Differential cleavage by γ-secretase results in the production of a small complement of different Aβ peptides: Aβ40 is the predominant species, whereas Aβ42 is the major component of senile plaques. Aβ42 is both more aggregation prone and neurotoxic than Aβ40 and has been hypothesized to represent the pathogenic Aβ species (5).

AMYLOID-BASED THERAPEUTICS A popular therapeutic strategy has been to decrease the production of Aβ by interfering with secretase processing. However, testing of the γ-secretase inhibitors semagacestat (LY-450139) and avagacestat (BMS-708163) did not show any prevention of cognitive decline (6), and target-based side effects resulting from the inhibition of overall γ-secretase function likely limit the utility of this approach (7). Focus has thus shifted to the inhibition of BACE1, and after a long period of frustrated efforts to design bioavailable and potent drugs targeting the large catalytic pocket of the enzyme (8), a new generation of potent BACE1 inhibitors is now undergoing clinical testing (Table 1). Recent data for two such inhibitors, E2609 and MK-8931, indicate that they are extremely effective at lowering Aβ production, resulting in up to 80–90% decreases in cerebrospinal fluid (CSF) levels in humans (9, 10). The high potency of these inhibitors may actually be a cause for concern, 382

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Table 1 Selected Alzheimer’s disease therapeutics Ongoing or recently completed Therapeutic, manufacturer

Mechanism

Published clinical or preclinical assessment (Reference)

clinical trial(s) [clinicaltrials.gov identifier(s)]


Antiamyloid therapeutics E2609, Eisai

BACE1 inhibitor

Phase I: 46–80% decreases in CSF Aβ (two-week trial) (9)

Phase I (NCT01600859)a

MK-8931, Merck

BACE1 inhibitor

Phase I: up to 94% decreases in CSF Aβ40 (two-week trial) (10)

Phase II/III (NCT01739348)

LY2886721, Eli Lilly

BACE1 inhibitor

Phase I: 58% decrease in CSF Aβ40 (two-week trial) (185)

Phase I (NCT01807026): completed in May 2013; Phase II (NCT01561430): terminated June 2013 due to abnormal liver biochemical tests (186)

AZD3293, AstraZeneca

BACE1 inhibitor

Not reported

Phase I (NCT01739647): completed in May 2013; Phase I (NCT01795339)

Solanezumab, Eli Lilly

Passive immunotherapy

Phase III: slowing of cognitive decline for mild AD (187, 188); increased Aβ in plasma, indicative of peripheral sink clearance (28)

Phase III (NCT01900665); Phase III prevention trials (DIAN trial: NCT01760005; A4 trial)

Crenezumab, Genentech

Passive immunotherapy, IgG4 backbone; also binds oligomers

Phase I: no VE at 10 mg/kg (n = 5) compared with 10% VE in patients receiving 1 mg/kg bapineuzumab (n = 29); dose-dependent increases in serum Aβ40 and Aβ42 (32)

Phase III prevention trial (API trial)

BIIB037, Biogen Idec

Passive immunotherapy; identified as an autoantibody in cognitively intact, very old donors

Recognition of aggregated but not monomeric Aβ (189)

Phase I (NCT01397539, NCT01677572)

CAD106, Novartis

Active immunotherapy; Aβ1–6 fragment

Phase I: good tolerance, but no change in CSF Aβ levels (43)

Phase II (NCT01097096, NCT00956410)a

ACC-001, Pfizer/Janssen


Not reported

Phase II (NCT00955409, ∗ NCT01238991) a

V950, Merck

Active immunotherapy

Not reported

Phase II completed in Jan. 2012 (NCT00464334)

Affitope AD02, AFFiRiS AG


Not reported

Phase II (NCT01117818)

RXR agonist

Rapid plaque clearance in APP/PS1 mice (44)

Phase II (NCT01782742)

GSK-3 inhibitor

Phase II: no effect on CSF tau or cognitive measures (84); Phase II microdosing trials: slowing of cognitive decline (86, 87)

N/A

R Bexarotene (Targretin ), Eisai

Tau therapeutics Lithium

(Continued )

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Table 1 (Continued) Therapeutic,

Published clinical or preclinical


manufacturer

Mechanism

Ongoing or recently completed clinical trial(s) [clinicaltrials.gov identifier(s)]

assessment (Reference)

Tideglusib (NP-12), Noscira

GSK-3 inhibitor

Phase II: no significant difference in cognitive measures versus placebo (190)

N/A

Thiamet-G

O-GlcNAcase inhibitor

Decrease in NFT load and neuronal loss in P301L mice (89)

N/A

Metformin

Antidiabetic; PP2A agonist

Decrease in tau phosphorylation and stimulation of neurogenesis in wild-type mice (92, 93)

Phase II completed in Feb. 2012 (NCT00620191)

Selenium salts

PP2A agonist

Decrease in tau pathology and increase in memory performance in mutant tau transgenic mice (96, 97)

Phase III (NTC00040378)

LMTXTM (TRx0237, a methylene blue derivative), TauRx

Tau aggregation inhibitor

Phase II: slowing of cognitive decline at lower doses (121)

Phase III (NCT01689233, NCT01689246)

Davunetide (NAP, AL-108), Allon Therapeutics

Microtubule-stabilizing agent

Phase II/III of progressive supranuclear palsy: no benefit (143)

N/A

Epothilone D (BMS-241027), Bristol-Myers Squibb

Microtubule-stabilizing agent

Reduction in tau pathology and cognitive deficits in mutant tau transgenic mice (144, 145)

Phase I (NCT01492374)

Masitinib, AB Science

Mast cell inhibitor

Phase II: slowing of cognitive decline when used as adjunct therapy to standard of care (159)

Phase III ongoing in Europe

p40 antibody [such as R ustekinumab (Stelara ), Janssen or briakinumab (ABT-874), Abbott Laboratories]

Proinflammatory cytokine inhibitor

Decreases in soluble Aβ and cognitive impairment (164)

N/A

CHF5074, Chiesi Pharmaceuticals/CereSpir

Microglial modulator

Phase II for MCI: improvements in several cognitive measures (162), decreases in CSF levels of TNF-α and sCD40L (163)

Phase II open-label extension (NCT01602393)

Deep brain stimulation

Neural circuit modulation using implanted electrodes

Open-label study (n = 6): increases in glucose metabolism and functional connectivity (174, 175)

Open-label study (NCT01559220), Phase I (NCT01608061)

Repetitive transcranial magnetic stimulation

Modulation of task-related circuits via stimulation during cognitive training

Randomized double-blind study (n = 15): improved cognitive measures (191)

Phase II (NCT01504958, NCT01179373, NCT00753662, NCT01334450, NCT01825330)

Transcranial direct current stimulation

Neural circuit modulation using external electrodes

Controlled double-blind study (n = 15): improved performance in a visual memory test (192)

Phase II (NCT01481558, NCT01887899)

Anti-inflammatory drugs

Symptomatic treatments

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Table 1 (Continued) Therapeutic,

Published clinical or preclinical


manufacturer

Ongoing or recently completed clinical trial(s) [clinicaltrials.gov identifier(s)]

assessment (Reference)

Mechanism

Lu AE58054, Lundbeck

5-HT6 R antagonist

Phase II: improved cognitive performance when used as adjunct to donepezil (193)

N/A

SAM-531, Wyeth

5-HT6 R antagonist

Phase II: early termination due to futility (NCT00895895)

N/A

EVP-6124, EnVivo Pharmaceuticals

α7 receptor agonist

Phase IIb: improved cognitive measures (180)

N/A

ORM-12741, Orion Pharma

α2c -adrenergic receptor antagonist

Phase IIa: improved cognitive measures when used as adjunct therapy to standard of care (183)

N/A

IVIg

Phase I and II: slowing of cognitive decline (35, 194); Phase III: no improvement in cognition as measured by ADAS-Cog, but a decrease in florbetapir signal (36)

N/A

IVIg

Phase II: no effect on cognitive measurements or Aβ40 levels in CSF or plasma (38)

Phase II (NCT01300728): ongoing, initial results show decreases in brain atrophy (195)

IVIg

N/A

Phase III (NCT01561053)

Antiepileptic

Phase II: reduced hippocampal hyperactivation, as seen on fMRI (140)

N/A

Other therapeutics GammagardTM , Baxter

R Octagam 10% and NewGam, Octapharma AG R Flebogamma , Grifols Biologicals R Levetiracetam (Keppra )

a

The listed trials are only the most recent of multiple same-phase trials. Abbreviations: AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s disease assessment scale-cognitive subscale; APP, amyloid precursor protein; Aβ, amyloid-β; BACE1, β-site amyloid precursor protein (APP)-cleaving enzyme 1; CSF, cerebrospinal fluid; fMRI, functional magnetic resonance imaging; GSK-3, glycogen synthase kinase 3; IgG4, immunoglobulin G4; IVIg, intravenous immunoglobulin; MCI, mild cognitive impairment; N/A, not available; NFT, neurofibrillary tangle; PP2A, protein phosphatase 2A; PS1, presenilin-1; RXR, retinoid X receptor; sCD40L, soluble CD40 ligand; TNF-α, tumor necrosis factor-α; VE, vasogenic edema.

as BACE1 has other substrates, and knockout mice exhibit behavioral changes (11, 12), display hypomyelination (13), and suffer from spontaneous seizures (14). Furthermore, knockout mice display defects in axon guidance (15, 16) and also develop vascular pathology in the retina (17). This latter finding mirrors one found in rats treated with the BACE1 inhibitor LY2811376, although the drug was subsequently found to induce the same retinal pathology in BACE1 knockout mice, suggesting that this was an off-target effect (18). Although many of the adverse effects from BACE1 inhibition in mice may be developmentally related, given past experience with γ-secretase inhibitors, careful safety monitoring in humans treated with BACE1 inhibitors is warranted.

Anti-Aβ Immunotherapy Active immunotherapy relies on the administration of an immunogen, often in combination with an adjuvant, to stimulate endogenous antibody production in the recipient, whereas passive www.annualreviews.org • Alzheimer’s Disease Therapeutics

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immunotherapy employs pregenerated antibodies. Three general mechanisms have been proposed to explain the clearance of Aβ from brain: (a) antibody penetration across the blood-brain barrier and opsonization of Aβ, followed by phagocytosis and the activation of complement; (b) the popularly subscribed-to peripheral sink mechanism, whereby the antibody-mediated clearance of Aβ in the periphery stimulates an equilibrating efflux of Aβ from the brain; and (c) the catalytic modification mechanism, whereby antibody binding to monomers induces a conformational change that lowers the oligomerization and/or fibrillization propensity (19). Aβ clearance likely occurs via all three mechanisms, although antibodies may cause preferential stimulation of one pathway, and the relative efficacy and safety of each is unknown. Although Aβ immunotherapy has been successful in animal models of AD, antibody penetration into the central nervous system is quite low, which is one reason that the peripheral sink hypothesis is an attractive mechanism to explain antibody-mediated clearance. APP transgenic mice intravenously injected with a single dose of radiolabeled 3D6, the founder mouse antibody of bapineuzumab (see below), showed a 140-fold enrichment for antibody levels in the serum versus the hippocampus 2 days postinjection. This decreased to only a 4-fold difference 27 days after injection, suggesting that whereas antibody delivery into the brain is relatively inefficient, its half-life there may be much higher (20). Passive Aβ immunotherapy has been the subject of several recent Phase III trials with negative, yet illuminating, outcomes. Bapineuzumab (Pfizer/Janssen) failed to improve cognitive measures in four pivotal Phase III trials of APOE4 (apolipoprotein E ε4 allele) or non-APOE4 carriers but did reduce amyloid plaque load, as assessed by Pittsburgh compound B amyloid imaging (21). Amyloid plaque load does not always correlate with the onset of dementia, and there is mounting evidence that Aβ oligomers, and not plaques, are the primary mediators of neurodegeneration in AD (22). The earlier Phase II trial also showed a reduction in CSF tau levels in treated individuals. All in all, the anticipated positive movement of Aβ and tau biomarkers in the setting of unchanged cognition is both difficult to explain and disheartening. Perhaps the dose-related side effect of the so-called amyloid-related imaging abnormalities (ARIA), associated with bapineuzumab (but less so with other Aβ antibodies), limited the delivery of an adequate dose to the test subjects, as ARIA is suggestive of vasogenic edema and microhemorrhages (23). Recently, N-terminal-truncated, pyroglutamylated (pE) forms of Aβ have been shown to be more stable, proaggregant, and neurotoxic than Aβ42 (24). Passive immunization with a pE3-Aβ antibody in an APP transgenic mouse model reduced total plaque load in both prevention and therapeutic trials in young and old mice, respectively (25), although effects on behavior were not examined. Further caution is warranted as the APP transgenic mice are imperfect models of AD (26). Solanezumab (Eli Lilly) also evidenced no overall slowing of cognitive decline in its own pair of Phase III trials, but aggregated data from exploratory analyses did demonstrate a treatment effect in patients with mild AD (discussed in 27). Furthermore, plasma levels of Aβ40 and Aβ42 were increased in a dose-dependent manner (28), suggesting the activation of peripheral sink clearance. The antibody has been selected for testing in two new prevention trials, one in patients with dominantly inherited AD mutations (the DIAN trial) and one in cognitively normal adults who display signs of amyloid accumulation (the A4 trial). The rationale behind prevention trials is predicated on (a) data from the solanezumab trial and other trials in which the most benefit was derived in patients with milder disease and (b) the finding that disease-related changes predate the onset of noticeable cognitive symptoms by more than 20 years (29–31). The Alzheimer’s Prevention Initiative trial will treat as-yet asymptomatic carriers of a dominant presenilin-1 (PSEN1) mutation in a large Colombian kindred with crenezumab, a unique immunoglobulin G4 (IgG4) antibody that has reduced effector function, thereby stimulating microglial clearance of Aβ in the absence


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of the activation of complement and the ensuing inflammatory response (32). This potentially makes crenezumab safer to use at higher doses. Amyloid-targeted immunotherapy is not limited to Aβ, as administration of a BACE1 antibody in nonhuman primates reduced Aβ levels in plasma and CSF (33). Furthermore, intravenous immunoglobulin (IVIg) therapy, traditionally associated with the treatment of autoimmune and inflammatory disorders, is currently under testing as a way to boost naturally occurring autoantibodies to Aβ (and tau), which are suggested to be underrepresented in AD patients compared with age-matched controls (34). GammagardTM (Baxter), which is pooled IVIg from healthy human donors, produced results in a small Phase II trial that suggested a slowing of cognitive decline (35), but these positive findings were not replicated in the recently completed Phase III trial (36). However, treatment was associated with both decreased plaque load in the brain, as detected by florbetapir imaging, and reduced plasma Aβ42 levels, although Aβ40 levels were unchanged (37). The GammagardTM results mirror those from a Phase II trial of 58 patients in which treatment with a different formulation of IVIg also demonstrated no effect on cognitive performance and no change in Aβ40 and Aβ42 CSF levels, but a reduction of plasma Aβ42 , suggesting that the expected clearance via the peripheral sink mechanism was not being induced (38). Active immunotherapy using immunization with the full Aβ1–42 peptide was terminated early in a Phase II trial (the AN1792 trial) owing to a low incidence (∼5%) of meningoencephalitis, thought to be the result of a strong T cell response (39, 40). Although initial analysis indicated a failure to improve cognitive measures, functional measures did improve in those who mounted a strong antibody response (41). In addition, postmortem analyses showed fewer plaques in treated patients, albeit with neither an apparent correlation to the subsequent severity of dementia nor an obvious reduction in tau pathology (42). CAD106 (Novartis), a new active vaccine containing a shorter fragment of Aβ (Aβ1–6 ) and designed to elicit a B cell rather than a T cell response, exhibited a good safety profile and antibody response in a Phase I trial, although CSF Aβ levels were unchanged compared with placebo (43).

Apoε4 and Aβ The APOE4 allele is the primary genetic risk factor for AD, and recent work has shown that R ) that targets one of the nuclear receptors regulating an agonist named bexarotene (Targretin Apoε4 expression, the retinoid X receptor (RXR), produces striking effects on Aβ measurements. A single dose reduced Aβ40 and Aβ42 levels in the interstitial fluid by 25% after 24 h in APP/PS1 mice (44). Knocking out Apoε4 abrogated the effects of bexarotene, and Aβ clearance was hypothesized to be mediated by microglial phagocytosis, as demonstrated in vitro. Bexarotene reversed behavioral deficits in young and old mice after as few as 7 days of treatment and reduced plaque burden by ∼75% in 6-month-old mice and 50% in 11-month-old mice following treatment for 2 weeks and 7 days, respectively. However, chronic treatment for 3 months (starting at 6 months of age) reduced soluble Aβ but not plaque burden, thus showing a troubling disconnect between chronic versus acute dosing. Four independent attempts to reproduce the initial findings were recently published, with the majority finding no significant effect of bexarotene on reducing Aβ levels or plaque burden (45–48). Bexarotene is already FDA-approved for the treatment of cutaneous T cell lymphoma, and its effect on amyloid clearance will be evaluated in a Phase II trial. Interestingly, RXR forms heterodimers with both peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptors (LXRs) to mediate transcriptional regulation, and the PPARγ agonists rosiglitazone and pioglitazone, antidiabetics that increase insulin sensitivity but attenuate the inflammatory response associated with microglial activation (49), produced negative outcomes in five AD trials (50). www.annualreviews.org • Alzheimer’s Disease Therapeutics

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TAU THERAPEUTICS Although hyperphosphorylated tau is the primary component of NFTs, the formulation of the amyloid cascade hypothesis relegated it to a secondary role in AD pathogenesis, and its importance as a drug target has historically been overshadowed by Aβ. However, interest in developing tau therapeutics is now on the rise, in part due to the negative trials targeting Aβ. A focus on tau likely characterizes the next major front in disease-modifying drug development for AD as well as diseases known as tauopathies, in which neurofibrillary pathology is the dominant neuropathological finding and in which mutations within tau and a growing list of genes cause rare inherited cases (see below).


Tau’s Role in Neurodegeneration Within the adult human brain, six major isoforms of tau are produced via alternative splicing of exons 2, 3, and 10; isoforms contain four microtubule (MT)-binding repeat sequences (4R tau) if exon 10 is included in the transcript, whereas its exclusion generates a tau protein with only three MT-binding repeats (3R tau) (51). In the healthy adult brain, 3R tau and 4R tau are approximately equimolar, and NFTs found in AD patients contain a mix of both isoforms (52). Tau can be phosphorylated at more than 30 residues, and whereas tau is phosphorylated under normal physiological conditions, pathological phosphorylation is associated with higher total phosphate content, as seen in tau isolated from AD brains (53), and phosphorylation of different residues. Abnormal and hyperphosphorylation of tau leads to dissociation from MTs and presumably initiates the perturbations leading to neuronal toxicity. These include the transition from a primarily axonal localization to mislocalization in the somatodendritic compartment, tau aggregation, and the formation of NFTs composed of hyperphosphorylated tau (51). It is not clear if phosphorylation directly promotes aggregation or if aggregation is an indirect effect of dysregulated interactions with other cellular factors. Ever since its downstream positioning in the amyloid cascade hypothesis, tau has proved to be a rich source of ongoing controversy. A key piece of evidence touted by supporters of tau’s undervaluation is the lack of correlation between severity of dementia and amyloid burden (54–56) in contrast to a robust correlation with NFT load (57). However, one of the strongest pieces of genetic evidence for the primacy of amyloid in the cascade hypothesis is the lack of FAD-associated mutations in tau: Autosomal dominant tau mutations do cause the neurodegenerative disorder FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) (58–62), but the disease presents with a notable absence of amyloid plaques together with different clinical presentations (63). In contrast, FAD mutations in APP or PSEN1 and PSEN2, which directly alter Aβ production or its aggregation properties, also result in the formation of NFTs in addition to amyloid deposits in the brain. These data indicate that alterations in tau alone are sufficient to mediate neurodegeneration but are insufficient to independently induce the full spectrum of AD pathology. Furthermore, tau aggregation (in the absence of tau mutations) is observed in many tauopathies, including AD, Pick’s disease, progressive supranuclear palsy, and chronic traumatic brain encephalopathy, suggesting that it may be a general feature of neurodegeneration. Intriguing experimental evidence indicates that Aβ administration can directly induce or promote tau pathology, here defined as either NFTs or abnormally phosphorylated, pretangle tau. Treatment of cultured neurons with fibrillar or oligomeric Aβ results in abnormal tau phosphorylation (64–66). Mice doubly transgenic for genes expressing mutant human APP and tau exhibit increased NFT pathology relative to mice carrying only the tau transgene (67), and injection of fibrillar Aβ42 into the brains of mice expressing mutant human P301L tau significantly 388

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increases NFT formation (68). Interfering with Aβ deposition also appears to modulate tau pathology: Administration of Aβ immunotherapy in 3xTg-AD mice, which express human APP and presenilin-1 protein (PS1) with FAD-causing mutations and human P301L tau (69), promotes decreases in early-stage accumulation of tau in the somatodendritic compartment (70), whereas administration of bapineuzumab in humans decreases CSF levels of phosphorylated tau (p-tau) (71). Furthermore, CSF Aβ42 levels in prodromal AD patients typically begin declining prior to increases in CSF total tau or p-tau (29, 30). Interestingly, the interplay of tau and Aβ also extends to non-Aβ amyloidosis, as in the example of tau pathology accelerated by Bri-amyloid peptide (72). In sum, these data suggest that changes in Aβ predate and perhaps precipitate tau pathology, thereby supporting the downstream positioning of tau in the amyloid cascade hypothesis.

Tau as a Therapeutic Target Although wild-type tau may not be an upstream trigger for neurodegeneration, it certainly appears to be a potent mediator or effector of Aβ-mediated neurodegeneration. Evidence to date suggests that Aβ deposition is more likely to act as a trigger or threshold barrier within the disease cascade, such that downstream processes, such as tau pathology, become independent of Aβ levels once triggered or are switched on and off as Aβ levels rise above or fall below a certain threshold (73). The assumption that the trigger or threshold point is relatively low yet the development of relevant brain lesions occurs well before the manifestation of cognitive impairment (30) may explain why Aβ-lowering therapies administered to patients who already have cognitive impairment have thus far failed to ameliorate disease progression. If a trigger or threshold scenario is truly in play, then therapeutic strategies targeting downstream effectors of Aβ are critical for halting disease progression once Aβ or Aβ-initiated abnormalities are already apparent, assuming that the effectors are responsible for a significant portion of the neurodegenerative phenotype and that ongoing deterioration is dependent on their continued presence. Evidence for the positioning of tau as a primary downstream mediator of Aβ-related neurodegeneration, and thus an attractive therapeutic target, is presented below. Alternatively, in a scenario wherein removal of the Aβ trigger does not alter disease progression or the spread of tau lesions once tau pathology has commenced, the efficacy of antiamyloid therapies will be contingent upon administration at an even earlier disease stage or even at the first onset of amyloid accumulation in brain. Cultured hippocampal neurons isolated from tau knockout mice exhibit little neuritic degeneration compared with neurons expressing endogenous murine tau or wild-type human tau on a murine tau knockout background (74). In contrast, Aβ-mediated inhibition of axonal transport was almost completely blocked in tau knockout neuronal culture (75), indicating that these effects are primarily mediated by tau alone. Two different APP transgenic mouse lines, when crossed with tau knockout mice, also show improved memory and protection from premature lethality in the absence of reduced Aβ expression or plaque load (76, 77). The toxicity of pyroglutamylated Aβ also appears to be dependent on tau, as mice overexpressing Aβ3(pE)-42 have dramatic neuronal loss by 3 months of age, whereas the same mice crossed to tau knockouts were protected (78). Notably, the tau knockout mouse has a relatively subtle phenotype given the protein’s physiological function (79), suggesting that tau inhibition may be relatively safe. Tau-mediated neurodegeneration also appears to be dependent on the continuous expression of tau. The rTg4510 mouse model, which conditionally expresses a human 4R tau variant carrying the P301L mutation, develops tau pathology in a gene-dosage-dependent manner that is accompanied by age-dependent memory deficits, dramatic loss of neurons within the hippocampus, and forebrain atrophy (80). Turning off expression of the tau transgene with doxycycline treatment at 2.5 months of age inhibits the progression of tau pathology, but doxycycline treatment at 4 months www.annualreviews.org • Alzheimer’s Disease Therapeutics

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of age or older is ineffective; in fact, the treated mice accumulate pathology to the same degree as do untreated mice. This finding may be due to incomplete suppression of transgenic tau expression, estimated to be approximately 2.5-fold that of endogenous murine tau mRNA expression following doxycycline treatment for 6–8 weeks. Nevertheless, rather surprisingly, doxycycline in 4-month-old mice prevented any further neuronal loss and improved memory function despite the increased tau pathology. This suggests that, like Aβ deposits in senile plaques, nonfibrillar oligomeric tau polypeptides—and not necessarily NFTs—are the toxic species causing memory loss. Furthermore, observations from both tau and APP transgenic mice indicate that memory loss and certain associated lesions are reversible. Similar results were found in proaggregant TauRD mice that inducibly express the 4R domain of tau with a K280 mutation that promotes aggregation (81). Ten months of transgene expression followed by 4 months of doxycycline suppression did not improve the level of tau aggregation, but behavioral deficits and long-term potentiation (LTP) at the mossy fiber–CA3 synapse were improved to control levels.


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Inhibiting Tau Hyperphosphorylation The sheer number of both phosphorylated tau residues and tau kinases have made it difficult to ascertain those that are pathologically relevant, and, combined with the off-target challenges stemming from kinase promiscuity, the fact that only a few tau kinase inhibitors have moved beyond the preclinical stage is not surprising. Notable among the major tau kinases, glycogen synthase kinase 3 (GSK-3) has been implicated in Aβ production and Aβ-mediated LTP inhibition (82, 83), suggesting that GSK-3 inhibition may affect neurodegeneration on multiple fronts. A 10week treatment trial of lithium, a nonspecific GSK-3 inhibitor used for the treatment of bipolar disorder, demonstrated no effect on levels of CSF tau and no observable cognitive benefit (84), and tideglusib (NP-12), an irreversible GSK-3 inhibitor from Noscira (85), did not meet the primary cognitive endpoint in a Phase IIb trial (Figure 1). Nonetheless, two human trials using low-dose lithium treatment over 12–15 months have reported a slowing of cognitive decline (86, 87). However, there is a narrow therapeutic window with lithium administration, and adverse effects are frequent. Glycosylation of serine/threonine residues in tau by O-linked N-acetylglucosamine (OGlcNAc) may compete with phosphorylation and serve as a protective modification that limits tau hyperphosphorylation. As O-GlcNAc modification is dependent on brain glucose availability, which is dysregulated in AD (88), decreased glycosylation may contribute to pathology. P301L tau transgenic mice (the JNPL3 model) that were chronically administered thiamet-G—an inhibitor of O-GlcNAcase, the enzyme mediating O-GlcNAc removal—displayed a decreased number of NFTs and were protected against neuronal cell loss (89). Interestingly, whereas O-GlcNAc modification reduced the amount of Sarkosyl-insoluble tau, abnormal phosphorylation of soluble tau was unaffected, suggesting that increased O-GlcNAc modification may inhibit tau aggregation in a hyperphosphorylation-independent manner. This was verified through the use of an in vitro tau aggregation assay. O-GlcNAc modification of histones has recently been linked to transcriptional regulation (90), and whether increasing O-GlcNAc may have unwanted global effects is unclear, although treatment was apparently well tolerated in mice. The state of tau hyperphosphorylation is also inversely regulated by the activity of phosphatases that dephosphorylate tau, in particular protein phosphatase 2A (PP2A) (91). The type 2 diabetes drug metformin also stimulates PP2A activity in vitro, consistent with the findings that metformin treatment of wild-type mice decreases tau phosphorylation (92). Metformin also enhances adult neurogenesis in both the subventricular and subgranular zones and improves performance of wild-type mice in the Morris water maze (93). However, metformin may also affect Aβ production via its ability to activate the 5 -AMP-activated 390

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b a Tau NMDAR

GSK-3

+PO4

+O-GlcNAc

PSD-95

O-GlcNAcase

+PO4 Fyn Tau

–O-GlcNAc


Lithium Tideglusib

Aberrant excitotoxicity Levetiracetam

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PP2A –PO4 Hyperphosphorylated tau

Metformin Selenium

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Axon

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PHF Methylene blue

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Figure 1 Therapeutic targeting of tau-mediated neurodegeneration. The top half of the figure represents a healthy neuron, whereas the bottom half depicts the situation in AD (Aβ pathology is not pictured here for the sake of simplicity). Green dots represent tau protein; drugs whose names appear in gray italics have not demonstrated efficacy in human trials. Under normal physiological conditions, tau phosphorylation is limited and localization is mostly axonal, whereas in AD, somatodendritic mislocalization of tau and the presence of NFTs are observed. (a) The hyperphosphorylation of tau, mediated by GSK-3 and other kinases, promotes its aggregation, which can be inhibited by GSK-3 inhibitors such as lithium or by tau aggregation inhibitors such as methylene blue. O-GlcNAc modification and phosphorylation of tau residues are mutually exclusive, and inhibiting the O-GlcNAcase using thiamet-G can therefore reduce tau phosphorylation. Dephosphorylation of tau is primarily mediated by PP2A, which can be stimulated by metformin and selenium. (b) Although tau is mostly an axonal protein, it is present at low concentrations in dendrites under normal conditions and appears to be responsible for the dendritic targeting of the Fyn kinase. Fyn phosphorylates subunit 2B of the NMDAR, strengthening an interaction with PSD-95, which is required for Aβ-mediated toxicity. The increased mislocalization of tau in AD has been hypothesized to result in the dendritic upregulation of Fyn levels, leading to enhanced excitotoxicity, which can be inhibited via the use of the epilepsy drug levetiracetam. Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; GSK, glycogen synthase kinase; NFT, neurofibrillary tangle; NMDAR, N-methyl-D-aspartate receptor; O-GlcNAc, O-linked N-acetylglucosamine; PHF, paired helical filament; PP2A, protein phosphatase 2A; PSD, postsynaptic density protein.

protein kinase (AMPK). AMPK activation, which is involved in numerous cellular pathways, mediates both Aβ-induced synaptotoxicity via phosphorylation of tau (94) and Aβ clearance via the induction of autophagy (95). Therefore, it is unclear if metformin treatment in humans will be beneficial or harmful with respect to Aβ. A Phase II trial examining metformin in amnestic mild cognitive impairment (aMCI) patients has recently been completed, and results should soon be forthcoming. Selenium salts also potentiate PP2A activity, thereby reducing tau phosphorylation www.annualreviews.org • Alzheimer’s Disease Therapeutics

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and NFT formation in tau transgenic mice (96, 97), and a Phase III trial testing selenium’s effect on the prevention of AD is set to be completed in 2014.

The Implications of Tau Immunotherapy


The practicality of tau immunotherapy was initially questionable, given that NFTs are intracellular aggregates and conventional wisdom held that antibodies are not internalized and are effective only against cell surface proteins. Yet active immunization using a phospho-tau peptide reduced the characteristic motor deficits of the P301L tau transgenic mouse model ( JNPL3) and decreased levels of p-tau (98). IgG was isolated from immunized mice, fluorescently labeled, and injected into the carotid artery of untreated JNPL3 mice, whereupon fluorescent staining of neurons colabeled with an antibody against p-tau suggested specific recognition of tau and intraneuronal uptake. Subsequent administration of tau antibodies in different mouse models has also demonstrated success in reducing tau pathology and improving behavior (99–101). Notably, improved performance in behavioral tests was observed in mice that expressed wild-type human tau (htau) in a mouse tau knockout background and that carried a human mutant PS1 transgene driving increased Aβ levels (102). This finding suggests that reductions in tau alone were sufficient to ameliorate disease, although the effect of the immunotherapy on Aβ levels was not assessed. Two studies have demonstrated decreased tau levels and improved behavior following passive tau immunotherapy, although both tested models developed motor deficits that precluded cognitive testing (103, 104). Although the classical view that antibody therapy is limited to extracellular proteins has been challenged by recent demonstrations of efficacy for antibodies targeting intracellular proteins (105, 106), how tau antibodies are taken up into the cells is still unclear, although lysosomal entry has been implicated in the intracellular targeting of α-synuclein antibodies (107). Tau antibodies may mediate clearance of extracellular tau, as increasing evidence points to the movement of tau into and out of cells. Mice with spatially restricted expression of P301L htau in the entorhinal cortex exhibit spreading tau pathology through synaptically connected regions, with tau aggregates containing both endogenous wild-type mouse tau and the human tau protein. This finding suggests that the human tau traversed synapses and seeded aggregation of the wild-type mouse tau (108, 109). Region-specific neurodegeneration was also observed, and in general the putative ordered spread of tau pathology previously observed in a classic series of human AD studies by Braak & Braak (110) was well modeled in these mice. Extracellular tau aggregates can be taken up by cells to induce tau aggregation within the cell in vitro (111, 112) and in vivo (113). Regarding the latter, injection of brain homogenates from P301S tau transgenic mice into Alz17 mice expressing wild-type human tau induced fibrillization at the injection sites and in neighboring regions. Induced aggregation following injection of tau oligomers purified from human AD brains was not observed in a tau knockout mouse, indicating that the effect is dependent on a true seeding mechanism (114). Many mechanisms have been proposed to explain the presence of extracellular tau, including release from dying neurons (111); secretion in presynaptic vesicles (115) or via exosomes (116); or constitutive, low-level secretion (∼0.3% of total tau in neurons derived from induced pluripotent stem cells) occurring independently of the classical secretory pathway (117). Tau secretion in cortical neuronal culture also appears to be stimulated by AMPA receptor–mediated activity (115), whereas on the receiving end, tau uptake appears to be mediated via endocytosis (118). The demonstration of extracellular tau has positive implications for tau immunotherapy, as it circumvents the problem of intracellular antibody access and provides an opportunity to prevent the spread of pathology, which likely has a causative role in worsening cognition. Although the amount of extracellular tau appears to be a small percentage of total tau, inhibiting these seeds may, surprisingly, be able to halt disease progression. 392

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Inhibiting Tau Aggregation Given that aggregation of tau is presumably critical for subsequent NFT formation, inhibition of tau aggregation is an obvious therapeutic target. Originally discovered as a chemical dye but subsequently used in the treatment of diseases ranging from malaria to bipolar disorder (119), the versatile methylene blue (methylthioninium chloride) is also an inhibitor of tau aggregation (120). A methylene blue derivative generated by TauRx Therapeutics (LMTXTM , TRx0237) is now in Phase III testing for both frontotemporal dementia and AD, buoyed by seemingly promising results R , TRx0014) (121). Thrice-daily oral from Phase II testing of an earlier formulation (Rember administration of 30- and 60-mg doses for 24 weeks reduced the rate of cognitive decline, whereas the higher 100-mg dose had no effect over placebo. These results might be better qualified as an equivocal success: First, the ineffectiveness of the high dose was claimed to be the result of limited uptake due to a binding between the drug and the housing capsule; second, some analyses included a comparison with a new placebo data set created post hoc by grouping the 100-mg and placebo arms. TauRx has yet to publish results from animal or human studies for its proprietary formulation, but others have demonstrated that chronic treatment with a very high dose of methylene blue in the rTg4510 tau transgenic mouse model reduced soluble tau levels but not preexisting tau pathology (122). Additionally, the high-dose treatment led to a modest improvement in Morris water maze performance. This was also observed following methylene blue treatment in the 3xTgAD mouse model (123), which furthermore exhibited reduced levels of soluble Aβ but no reduction in phosphorylation of tau. In fact, methylene blue’s pleiotropism may contribute further advantages to its use against AD, as it inhibits Aβ fibrillization (124); promotes tau degradation by inhibiting the ATPase activity of the chaperone protein Hsp70 (125); and acts as an alternative electron acceptor in the electron transfer chain (126), likely conferring neuroprotection via reduction of oxidative stress and stimulation of oxygen metabolism and cerebral blood flow (127, 128). Indeed, a recent report has suggested a possible mechanism, as methylene blue and its metabolites induced oxidation of tau and thus decreased the aggregation propensity of the monomeric form (129).

Inhibition of Neuronal Excitotoxicity Exciting recent data have illuminated a mechanism that may underlie tau’s ability to serve as a downstream effector of Aβ. AD patients appear to have a higher incidence of unprovoked seizures than do age-matched controls (130, 131), and several APP transgenic mouse lines exhibit unprovoked seizures and hyperexcitability (132, 133) as well as increased severity of drug-induced seizures, which are likely linked to excessive neuronal stimulation by Aβ (134, 135). This Aβ-mediated excitotoxicity, in turn, appears to be dependent on tau. One of tau’s many binding partners is the Src tyrosine kinase Fyn, which strengthens the interaction of the N-methyl-D-aspartate receptor (NMDAR) with postsynaptic density protein 95 (PSD-95) in the postsynaptic density via phosphorylation of the NMDAR subunit 2 (NR2b). Normally, tau is preferentially localized to axons, but in human AD patients, tau exhibits increased somatodendritic mislocalization (136), which may lead to increased postsynaptic localization of Fyn and overexcitation of the NMDAR. The use of APP transgenic mice crossed to tau knockout mice (hAPPJ20/Tau−/− ) showed that both somatodendritic targeting of Fyn and the NMDAR–PSD95 interaction are tau-dependent (77). Furthermore, tau knockout in the APP23 mouse model led to a reduction in drug-induced seizure severity, without affecting Aβ levels or plaque deposition. T-maze memory performance was improved in the absence of tau, a finding also reproduced by intracerebroventricular administration of a peptide inhibitor of the NR2b–PSD-95 interaction, suggesting that NMDAR overstimulation is at least partially responsible for memory deficits. www.annualreviews.org • Alzheimer’s Disease Therapeutics

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Neuronal network dysfunction may also result from an overstabilized NR2b–PSD-95 interaction, as reported in an independent study in the hAPPJ20/Tau−/− mouse model (137). The study found a reduction in network excitability, as assessed by a reduction in PTZ-induced seizure severity and epileptiform spike activity in freely moving mice. Defects in synaptic transmission and plasticity in the hippocampus were also reversed by tau depletion. Interestingly, treatment with the antiepileptic drug levetiracetam is beneficial in both APP transgenic mice and mild cognitive impairment (MCI) patients. Levetiracetam treatment reduced aberrant spikes in EEG activity in hAPPJ20 mice; improved performance in hippocampusdependent learning and memory tasks; and restored LTP and synaptic transmission strength in hippocampal slices, again in the absence of changes in Aβ pathology (138). It should be cautioned that human patients can develop drug tolerance after initial exposure to levetiracetam (139), and, interestingly, hAPPJ20 mice treated with high doses did not derive the same benefits as those derived by the low-dose group. In humans with aMCI, hippocampal hyperactivation can be observed via functional magnetic resonance imaging (fMRI), whereas patients with late aMCI or early AD exhibit the reverse, suggesting that early overstimulation may contribute to later dysfunction and memory impairment. In patients with aMCI, two weeks of low-dose levetiracetam reduced general hippocampal activation, reduced activation of the dentate gyrus and CA3 hippocampal subregions, and improved performance in a memory task dependent on pattern separation and pattern completion mediated by DG-CA3 function (140). As it is unclear if the effects of hippocampal hyperactivity are reversible, an antiepileptic intervention may be most helpful in the early stages of the disease.


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Countering a Loss of Function in Tau: Microtubule Stabilization A dysregulation of MT stability in AD may be an important contributor to neurodegeneration, as hyperphosphorylation releases tau from MTs and sequestration of tau into NFTs may further contribute to MT destabilization (141). Whether a toxic gain of function better explains tau’s ability to mediate neurodegeneration has been a topic of some debate, especially given that the normal phenotype of the tau knockout mouse suggests functional redundancy (142), and, as described below, therapeutics aimed at compensating for the loss-of-function mechanism have produced mixed results. The MT-stabilizing octapeptide NAP (davunetide, AL-108), shown to improve memory and tangle pathology in P301S/K257T tau transgenic mice, recently failed to provide clinical benefit to progressive supranuclear palsy patients in a Phase II/III trial (143). Administration of the MT-stabilizing agent epothilone D in P301S tau transgenic mice and rTg4510 mice improved cognitive performance, reduced neuronal loss in the hippocampus, and decreased levels of abnormally phosphorylated tau, suggesting that MT stability contributes to tau pathology (144, 145). The use of MT-stabilizing drugs as antimitotic cancer chemotherapy is offset by rather severe side effects, but amelioration in the P301S model was achieved with very low doses of epothilone D and in the apparent absence of toxicity (145). Phase I testing of epothilone D (BMS-241027) in patients with mild AD is currently under way.

THERAPEUTICS TARGETING OTHER PATHOPHYSIOLOGICAL MECHANISMS Inflammation and Alzheimer’s Disease That aberrant inflammatory responses are consistently found in brains of AD individuals has long been recognized, and whether these changes represent an important contribution to the pathophysiology of AD is debatable (146). Epidemiological studies have indicated a correlation 394

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between regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and a decrease in the risk of developing AD (147), and the expression of proinflammatory cytokines such as IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α) is upregulated in the CSF and brain tissue of AD patients (148). Furthermore, genome-wide association studies have identified risk variants for late-onset AD in various genes with roles in inflammation, suggesting that inflammation is not only a result of AD but also a factor in disease development or progression (149). There is conflicting evidence regarding the role of microglial activation in Aβ clearance, as genetic manipulations of microglial activation result in microglial clearance of Aβ deposits via phagocytosis or in increased amyloid deposition (150), possibly as a result of the release of inflammatory cytokines that can mediate cellular damage if continuously expressed, as during chronic inflammation (151). Therapeutic intervention in inflammation is therefore by necessity a delicate dance between the preservation and inhibition of helpful and harmful inflammatory responses. Although the epidemiological link between NSAIDs and AD has been upheld in many studies, clinical trials have mostly failed to replicate this protective effect (152–154). γ-secretase-modulating activity, or the shifting of the enzyme’s cleavage preference to reduce the production of the amyloidogenic Aβ42 , was first observed in a subset of NSAIDs when used at high doses (155), indicating that NSAIDs may protect against AD in additional ways besides their anti-inflammatory activity. Tarenflurbil, the R-enantiomer of flurbiprofen that lacks anti-inflammatory properties, failed to produce a positive outcome in Phase III testing (156), although the drug’s weak potency and low brain penetrance are complicating factors (157). A large prevention trial associated the use of naproxen or celecoxib with increased AD risk in patients diagnosed with AD early in the aborted trial, but during follow-up after termination of drug treatment, individuals with higher baseline cognitive measures showed improvement after taking naproxen for two to three years (158). Therefore, the outcome of NSAID treatment in presymptomatic individuals is decidedly inconclusive. Masitinib, a tyrosine kinase inhibitor that inhibits mast cell differentiation and degranulation, had promising results as an adjunct therapy to the current standard of care in a small Phase II trial, slowing cognitive decline after 12 or 24 weeks of twice-daily treatment (159). MMSE (mini–mental state examination) scores for the masitinib subjects were stable, whereas they worsened in the placebo group, and masitinib will be evaluated in a Phase III trial in mild to moderate AD. CHF5074, an NSAID derivative initially developed as a γ-secretase modulator, has been reclassified as a novel, first-in-class microglial modulator for AD treatment, on the basis of its ability to reduce both amyloid burden and microglial activation (160, 161). Interim results from an ongoing Phase II trial in patients with MCI indicated that CHF5074 treatment led to improvements over baseline in several cognitive measures (162) and reduced inflammatory marker levels in the CSF (163). More focused anti-inflammatory agents may also hold promise. When APP/PS1 mice were crossed with mice deficient in p40, a subunit of both the IL-12 and IL-23 proinflammatory cytokine receptors, they exhibited decreased amyloid plaque load (164), suggesting that suppression of these inflammatory mediators contributes to Aβ deposition. Intracerebroventricular administration of p40 antibody decreased soluble levels of Aβ and ameliorated the mild cognitive deficits found in this model, although in contrast to the genetic depletion, immunotherapy did not affect the insoluble amyloid burden. Levels of p40 were elevated in the CSF of AD patients relative to controls, and ustekinumab and briakinumab, two antibodies against p40 that are already FDA-approved for the treatment of psoriasis, may be attractive candidate therapeutics for AD.

Symptomatic Treatments Current commonly used treatment options for AD include the cholinesterase inhibitors donepezil, rivastigmine, and galantamine and the NMDA antagonist memantine. These provide modest www.annualreviews.org • Alzheimer’s Disease Therapeutics

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symptomatic benefits at best, but they have not been concretely demonstrated to significantly slow cognitive worsening (165). Delaying the onset of disease even incrementally would significantly reduce the economic and social burden of the disease. The total cost of dementia in the United States was estimated at $159–215 billion in 2010 and is expected to more than double to $379– 511 billion by 2040 (166); a treatment that would delay onset for five years is estimated to reduce AD costs by $447 billion over 40 years (167). Whereas disease-modifying strategies are discussed in the preceding sections, below we present several approaches for symptomatic relief. Perturbations in the connectivity and activation of the default mode network (DMN) are commonly observed in AD patients through molecular imaging techniques such as fMRI and FDGPET (fludeoxyglucose positron emission tomography) (168). The DMN incorporates functionally connected brain regions that were originally recognized on the basis of their activation during passive resting states and their corresponding deactivation during attention-demanding cognitive tasks (169). The DMN is disrupted with aging, and this effect is more pronounced in AD patients (168) or even in APOE4 carriers who have not developed plaque pathology (170). Deep brain stimulation (DBS), an approved treatment for Parkinson’s disease and essential tremor, uses surgical implantation of indwelling electrodes connected to a pulse generator (often compared to a cardiac pacemaker) to stimulate or suppress the activity of specific circuits within the brain (171). Improvements in short-term memory function following DBS have been observed in APP transgenic mice (172), and DBS has improved spatial memory in wild-type mice by stimulating neurogenesis (173). A small open-label, noncontrolled Phase I trial in six patients with mild AD concomitantly taking cholinesterase inhibitors showed that DBS of the fornix and hypothalamus for one year increased cortical glucose metabolism (as seen on PET scans) and improved functional connectivity (as seen through fMRI analysis), with some indication of slowed cognitive decline (174, 175). Two other somewhat related but noninvasive modalities, repetitive transcranial magnetic stimulation and transcranial direct current stimulation, are also being further investigated in humans (Table 1). It is unclear whether these rather heroic measures, even if somewhat effective, can be broadly administered to affected individuals. A well-documented literature supports the idea that a larger cognitive reserve, built up during a lifetime of mental activity and physical exercise, can delay the onset (but not the progression) of AD (176). Environmental enrichment and voluntary physical activity promote neurogenesis in animal models (177). In addition to behavioral interventions, the use of selective 5-HT6 R (serotonin receptor) antagonists in animal models has resulted in cognitive enhancement (178), and Lu AE58054 (179) was recently found to significantly improve cognitive performance in a Phase II trial of AD patients also taking donepezil. Phase II testing of another 5-HT6 R antagonist, SAM-531, was terminated early owing to futility of the intervention. Another drug that succeeded in improving cognitive function in a Phase IIb trial is EVP-6124 (180), an agonist of the nicotinic α7 acetylcholine receptor that has been implicated in memory function (181). Antagonism of the α2c -adrenergic receptor with ORM-12741, previously shown to improve memory performance in animal models (182), stabilized or even slightly improved memory function in patients with moderate AD who also were taking cholinesterase inhibitors or memantine (183).


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CONCLUSIONS Whereas many therapeutic approaches have failed to slow or halt the progression of AD in clinical trials, inadequate testing paradigms may have contributed to negative outcomes, and the new push toward early treatment and prevention trials holds promise for the future. The recent proposal by the FDA to allow approval of any AD therapies that show improvement in cognitive performance or biomarkers of such, as opposed to earlier requirements that therapies demonstrate both functional 396

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and cognitive improvement (184), highlights both the increasing acceptance that earlier is better and the urgent need for effective therapies and accurate correlates of protection. Optimism may be thin on the ground after the failure to show efficacy in several high-profile Phase III trials, yet several promising candidates are currently in testing, including interventions targeting tau as a key downstream effector of the amyloid cascade. Many of these drugs have effects on multiple pathways involved in pathophysiology, and the use of multiple drugs targeting different cellular pathways may succeed in halting disease progression through a combinatorial approach.


DISCLOSURE STATEMENT This work was supported, in part, by National Institutes of Health Grants AG 20206 (to E.H.K.), AG 32179 (to E.H.K.), and AG 00216 (to K.C.). E.H.K. is coinventor on a patent relating to AD therapeutics. E.H.K. has served as a consultant for Pfizer Inc. (including Wyeth Research), GlaxoSmithKline, and Theravance Inc.

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174. Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, et al. 2010. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann. Neurol. 68(4):521–34 175. Smith GS, Laxton AW, Tang-Wai DF, McAndrews MP, Diaconescu AO, et al. 2012. Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. Arch. Neurol. 69(9):1141–48 176. Stern Y. 2012. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 11(11):1006–12 177. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, Van Praag H. 2010. When neurogenesis encounters aging and disease. Trends Neurosci. 33(12):569–79 178. Upton N, Chuang TT, Hunter AJ, Virley DJ. 2008. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 5(3):458–69 179. Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, et al. 2010. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int. J. Neuropsychopharmacol. 13(8):1021–33 180. EnVivo Pharmaceuticals. 2012. EnVivo Pharmaceuticals announces statistically significant improvement in cognition and clinical function in Phase 2b clinical trial in Alzheimer’s disease. News Release, July 18 181. Levin ED. 2002. Nicotinic receptor subtypes and cognitive function. J. Neurobiol. 53(4):633–40 182. Marien MR, Colpaert FC, Rosenquist AC. 2004. Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res. Brain Res. Rev. 45(1):38–78 183. Orion Corp. 2013. Orion Corporation presented promising Phase II data for new Alzheimer’s disease drug at AAN Annual Meeting. News Release, Mar. 21 184. Kozauer N, Katz R. 2013. Regulatory innovation and drug development for early-stage Alzheimer’s disease. N. Engl. J. Med. 368:1169–71 185. Martenyi F, Dean RA, Lowe S, Nakano M, Monk S, et al. 2012. BACE inhibitor LY2886721 safety and central and peripheral PK and PD in healthy subjects (HSs). Alzheimer’s Dement. 8(4 Suppl.):P583–84 186. Eli Lilly and Co. 2013. Lilly voluntarily terminates Phase II study for LY2886721, a beta secretase inhibitor, being investigated as a treatment for Alzheimer’s disease. News Release, June 13 187. Doody RS. 2012. Phase 3 studies of solanezumab for mild to moderate Alzheimer’s disease. Presented at Am. Neurol. Assoc. 2012 Annu. Meet., Oct. 7–9, Boston 188. Hake A, Siemers E, Carlson C, Estergard W, Sundell K, et al. 2013. Efficacy and safety of intravenous solanezumab in patients with mild to moderate Alzheimer’s disease: results of two phase 3 studies. Neurology 80(Meet. Abstr. 1):S24.006. http://www.neurology.org/cgi/content/meeting_abstract/80/1_ MeetingAbstracts/S24.006 189. Grimm J. 2012. Immunotherapy with recombinant human-derived antibodies. Presented at 8th Int. Winter Conf. Alzheimer’s Dis. Program, Dec. 7–10, Zuers, Austria 190. Noscira. 2012. Noscira announces results from ARGO Phase IIb trial of tideglusib for the treatment of Alzheimer’s disease. News Release, Oct. 11 191. Rabey JM, Dobronevsky E, Aichenbaum S, Gonen O, Marton RG, Khaigrekht M. 2013. Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: a randomized, double-blind study. J. Neural Transm. 120(5):813–19 192. Boggio PS, Ferrucci R, Mameli F, Martins D, Martins O, et al. 2012. Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease. Brain Stimul. 5(3):223–30 193. Lundbeck. 2012. Lundbeck’s Lu AE58054 meets primary endpoint in large placebo-controlled clinical proof of concept study in people with Alzheimer’s disease. News Release, May 29 194. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, et al. 2009. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol. Aging 30(11):1728–36 195. Kile S, Au W, Parise C, Low R. 2013. Initial findings of a randomized double-blinded placebo-controlled study of intravenous immunoglobulin in mild cognitive impairment due to Alzheimer disease. Neurology 80(Meet. Abstr. 1):P01.013. http://www.neurology.org/cgi/content/meeting_abstract/80/1_ MeetingAbstracts/P01.013

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Annual Review of Pharmacology and Toxicology


Contents

Volume 54, 2014

Learning to Program the Liver Curtis D. Klaassen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication Mathias Rask-Andersen, Surendar Masuram, and Helgi B. Schiöth p p p p p p p p p p p p p p p p p p p p p p p 9 Engineered Botulinum Neurotoxins as New Therapeutics Geoffrey Masuyer, John A. Chaddock, Keith A. Foster, and K. Ravi Acharya p p p p p p p p p p p p27 Pharmacometrics in Pregnancy: An Unmet Need Alice Ban Ke, Amin Rostami-Hodjegan, Ping Zhao, and Jashvant D. Unadkat p p p p p p p p p53 Antiparasitic Chemotherapy: From Genomes to Mechanisms David Horn and Manoj T. Duraisingh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71 Targeting Multidrug Resistance Protein 1 (MRP1, ABCC1): Past, Present, and Future Susan P.C. Cole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95 Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds Mark J. Niciu, Ioline D. Henter, David A. Luckenbaugh, Carlos A. Zarate Jr., and Dennis S. Charney p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 119 Environmental Toxins and Parkinson’s Disease Samuel M. Goldman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 141 Drugs for Allosteric Sites on Receptors Cody J. Wenthur, Patrick R. Gentry, Thomas P. Mathews, and Craig W. Lindsley p p 165 microRNA Therapeutics in Cardiovascular Disease Models Seema Dangwal and Thomas Thum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185 Nanocarriers for Vascular Delivery of Anti-Inflammatory Agents Melissa D. Howard, Elizabeth D. Hood, Blaine Zern, Vladimir V. Shuvaev, Tilo Grosser, and Vladimir R. Muzykantov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 205

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G Protein–Coupled Receptors Revisited: Therapeutic Applications Inspired by Synthetic Biology Boon Chin Heng, Dominique Aubel, and Martin Fussenegger p p p p p p p p p p p p p p p p p p p p p p p p p p 227 Cause and Consequence of Cancer/Testis Antigen Activation in Cancer Angelique W. Whitehurst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 251 Targeting PCSK9 for Hypercholesterolemia Giuseppe Danilo Norata, Gianpaolo Tibolla, and Alberico Luigi Catapano p p p p p p p p p p p p p 273


Fetal and Perinatal Exposure to Drugs and Chemicals: Novel Biomarkers of Risk Fatma Etwel, Janine R. Hutson, Parvaz Madadi, Joey Gareri, and Gideon Koren p p p p 295 Sodium Channels, Inherited Epilepsy, and Antiepileptic Drugs William A. Catterall p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Chronopharmacology: New Insights and Therapeutic Implications Robert Dallmann, Steven A. Brown, and Frédéric Gachon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339 Small-Molecule Allosteric Activators of Sirtuins David A. Sinclair and Leonard Guarente p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 363 Emerging Therapeutics for Alzheimer’s Disease Karen Chiang and Edward H. Koo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 381 Free Fatty Acid (FFA) and Hydroxy Carboxylic Acid (HCA) Receptors Stefan Offermanns p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 407 Targeting Protein-Protein Interaction by Small Molecules Lingyan Jin, Weiru Wang, and Guowei Fang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 435 Systems Approach to Neurodegenerative Disease Biomarker Discovery Christopher Lausted, Inyoul Lee, Yong Zhou, Shizhen Qin, Jaeyun Sung, Nathan D. Price, Leroy Hood, and Kai Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457 GABAA Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism Uwe Rudolph and Hanns Möhler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 483 Role of Hepatic Efflux Transporters in Regulating Systemic and Hepatocyte Exposure to Xenobiotics Nathan D. Pfeifer, Rhiannon N. Hardwick, and Kim L.R. Brouwer p p p p p p p p p p p p p p p p p p p 509 Turning Off AKT: PHLPP as a Drug Target Alexandra C. Newton and Lloyd C. Trotman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 537 Understanding and Modulating Mammalian-Microbial Communication for Improved Human Health Sridhar Mani, Urs A. Boelsterli, and Matthew R. Redinbo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 559

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Pharmaceutical and Toxicological Properties of Engineered Nanomaterials for Drug Delivery Matthew Palombo, Manjeet Deshmukh, Daniel Myers, Jieming Gao, Zoltan Szekely, and Patrick J. Sinko p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 581 Indexes Cumulative Index of Contributing Authors, Volumes 50–54 p p p p p p p p p p p p p p p p p p p p p p p p p p p 599


Cumulative Index of Article Titles, Volumes 50–54 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 602 Errata An online log of corrections to Annual Review of Pharmacology and Toxicology articles may be found at http://www.annualreviews.org/errata/pharmtox

Contents

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Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics.

PPARγ signaling and emerging opportunities for improved therapeutics.

Emerging therapeutics for the treatment of diabetic nephropathy.

Smoldering Multiple Myeloma: Emerging Concepts and Therapeutics.

microRNA Therapeutics in Cancer - An Emerging Concept.

Primary Immunodeficiency Diseases: Current and Emerging Therapeutics.

Splicing therapeutics for Alzheimer's disease.

MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics.

Antibody therapeutics for Ebola virus disease.

Personalized gene silencing therapeutics for Huntington disease.

ACTRIMS, Amsterdam, 2011.

Cold-adapted proteases as an emerging class of therapeutics.

Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics.

Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics.

Emerging drugs for celiac disease.

Emerging drugs for coeliac disease.

Recent discoveries and emerging therapeutics in eosinophilic esophagitis.

Emerging insights into barriers to effective brain tumor therapeutics.

Biomaterials and emerging anticancer therapeutics: engineering the microenvironment.

Emerging applications of exosomes in cancer therapeutics and diagnostics.

The future of osteoarthritis therapeutics: emerging biological therapy.

Melatonin and abeta, macular degeneration and alzheimers disease: same disease, different outcomes?

Low temperature plasmas as emerging cancer therapeutics: the state of play and thoughts for the future.

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics.