MENU

en menu

Articles

  • KSBNS 2024

Article Tools

View Full Text Abstract
Article as PDF Print this Article
Pubmed PMC
PubReader Export to Citation
Email Alerts Open Access

Share this article on :

Stats or Metrics

Article

Review

Exp Neurobiol 2010; 19(3): 120-131

Published online December 31, 2010

https://doi.org/10.5607/en.2010.19.3.120

© The Korean Society for Brain and Neural Sciences

Drug Development for Alzheimer's Disease: Recent Progress

Wonjin Ji and Ilho Ha*#

Institute for Brain Science and Technology (IBST)/Graduate Program in Neuroscience, Inje University, Busan 614-735, Korea

Correspondence to: #Present address: Theragen Bio Institute, GSBC Building, Suwon 443-776, Korea
*To whom correspondence should be addressed.
TEL: 82-31-259-6500, FAX: 82-31-259-6511
e-mail: ilhoha@therabio.org or ilhoha@yahoo.com

Abstract

Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development.

Keywords: Alzheimer's disease, AՂ,, tau, drug, clinical trial

INTRODUCTION

In the last century, the world transitioned from a young to aging population that increasingly suffers from major health problems such as infectious disease to chronic illness. Especially, neurodegenerative diseases are a major concern in aged countries. Among these diseases, Alzheimer's disease (AD) is the most prevalent with the number of the patients about 30 million worldwide, and this will reach more than 80 million in 2040 (Prince and Jackson, 2009).

AD, the most common cause of dementia, is a chronic disorder characterized by a progressive decline in cognitive function. Major pathological hallmarks include extensive neuronal loss, formation of intracellular neurofibrillary tangles (NFT) and extracellular deposition of β-amyloid peptides (Aβ). Despite extensive research, the cause of sporadic AD (more than 90% of all AD) is still unknown (Brunden et al., 2009; Bettens et al., 2010). Additionally, there are no true disease-modifying drugs in the market; drugs currently available are acetylcholine esterase inhibitors and a N-methyl D-aspartic acid (NMDA) receptor modulator, which are for symptomatic treatments only (Mangialasche et al., 2010).

Amyloid cascade theory and tauopathy have been proposed as the cause of AD based on two pathological hallmarks (NFT and Aβ). Accordingly, drug development has focused on the removal of Aβ and NFT from the brain. However, many drugs are currently under development based on other theories of the etiology of AD. Disease-modifying treatments are highly desirable but are thus far unsuccessful. The failed efficacy of recent multicenter clinical trials could be due to systematic and random measurement errors, as well as improper design, monitoring, analysis and interpretation (Becker and Greig, 2008). However, several of the compounds currently being developed could become drugs with additional technical innovations and methodological improvements for clinical trials.

The purpose of this article was to provide a brief overview on the current development of drugs for Alzheimer's disease and offer some prospective comments.

DRUG DEVELOPMENT TO TARGET Aβ (TABLE 1)

The amyloid cascade hypothesis is a compelling model that the aberrant production of Aβ 1-42 is the causative agent in the pathogenesis of AD. There are many strategic approaches to reduce the level of toxic Aβ 1-42 in the brain: (1) immunotherapy, (2) γ-secretase inhibitors, (3) β-secretase inhibitors, (4) Aβ oligomerization inhibitors, (5) inhibitors that prevent transport of Aβ from blood to the brain, (6) degradation of Aβ.

Immunotherapy

Several immunotherapies targeting Aβ have been conducted in clinical trials based on previous data on improved cognition in mouse models of AD (Dodart et al., 2002; Kotilinek et al., 2002; Lee et al., 2006). The first generation vaccine targeting Aβ was AN-1792, but its phase II clinical trial (CT) was discontinued due to the development of aseptic meningoencephalitis in 6% of patients (Gilman et al., 2005). The second-generation vaccine, ACC-001, was developed to avoid an inflammatory response and currently undergoing phase II CTs (Fagan, 2008a).

Passive immunizations have also been attempted. Among them, bapineuzumab, a humanized monoclonal antibody targeting Aβ, completed its phase II trial in 234 mild to moderate AD patients. Although it failed to show a clear clinical benefit, it moved to phase III CTs based on its safety and biomarker data generated by positron emission tomography (PET) (Strobel, 2008a). Recently its highest dose (2 mg/kg) was abandoned to reduce the risk for vasogenic edema (Strobel, 2009) but the interim data of phase III show reduction of amyloid load in the brains (Landhuis, 2010b). Like bapineuzumab, LY2062430 (Solanezumab) and PF-04360365 are monoclonal antibodies against Aβ peptide. The former completed its phase I and II trials and is currently in phase III (Siemers et al., 2010; CT 1 and CT 2 in ref.), whereas the latter completed phase I CTs and is undergoing phase II (Landhuis, 2009a; CT 3 in ref.).

Since a mixture of intravenous immunoglobulin (IVIg) of human blood contains the antibody against Aβ it could be used to quench a pool of Aβ (Dodel et al., 2002). In a small trial (24 people) for 18 months, IVIg (Gammagard) slowed clinical decline and protected brains against shrinkage. The mechanism for protection against AD could be due to direct targeting of Aβ by IVIg or an indirect immunomodulatory effect. A larger (360 AD patients) multi-center phase III trial is underway (Dodel et al., 2010; Fagan, 2010e). There are several active (AFFITOPE AD01 and AFFITOPE AD02, GSK933776A, MABT5102A and V950) as well as passive (R1450 and RN 1219) immunizations for Aβ under development currently (Lemere and Masliah, 2010).

γ-secretase inhibitors

Gamma-secretase is the final enzyme involved in the cleavage of amyloid precursor protein (APP) in the membrane, and it consists of a complex of four different proteins (presenilin, nicastrin, Aph-1 and Pen-2) (Takasugi et al., 2003; Wolfe, 2008). Among the four proteins in the complex, presenilin is the key enzyme that cleaves APP. However, γ-secretase cleaves other proteins (more than 50 protein substrates) in addition to APP, which makes finding an APP-specific inhibitor for γ-secretase very difficult (Beel and Sanders, 2008). Furthermore, presenilin is an unusual protein with more than 150 mutations in its gene that are autosomal dominant for the early onset of AD (PS1 mutation database in ref.). Many mutations discovered in earlier studies increase the release of Aβ 42, a neurotoxic form of Aβ peptides, in the brain. Accordingly, strategies for blocking its enzymatic activity have been intensely pursued. Regarding γ-secretase, substrate specificity is challenging because it cleaves many substrates such as Notch, which is an important regulator in many physiological processes (De Strooper et al., 1999).

The first in vivo proof of γ-secretase as a therapeutic target of AD was obtained using DAPT in a transgenic mouse model, which resulted in reduced Aβ in the brain after oral administration (Dovey et al., 2001; Lanz et al., 2003). LY411575 showed adverse effects on the immune system and intestine in a mouse model, and it was later found to have poor selectivity for APP over Notch (Wong et al., 2004). Additionally, the side effects of LY411575 have prevented the viability of a clinical trial. Later, LY450139 (Semagacestat) was developed to avoid such adverse side effects. Phase II trials with LY450139 was unusual to estimate the clinical endpoint by measuring biomarkers (e. g. the plasma concentration of Aβ) rather than measuring the cognitive or clinical improvements (Strobel, 2007b). Even though LY450139 did not have excellent selectivity for APP over Notch (E50=1:2.8), it did move on to phase III trials but halted due to the treatment group showing faster decline in cognition than the placebo group (Strobel, 2007a; Martone et al., 2009; Fagan, 2010d).

BMS-299897 and MRK-560 were developed for improvement of substrate selectivity of γ-secretase, and they have been shown to be effective in animal models without any sign of Notch inhibition (Barten et al., 2005; Best et al., 2007). However, they were not found in the stage of clinical trials. GSI-953 (Begacestat) also has excellent selectivity for APP cleavage over Notch (E50=1:16.8) (Mayer et al., 2008). Phase I CTs for GSI-953 have been conducted but no data have been disclosed.

In addition to classical inhibitor approaches, compounds that modulate the enzymatic activity of γ-secretase have been developed. Certain non-steroidal anti-inflammatory drugs (NSAIDs) have been found to reduce the amount of toxic Aβ 42 (McGeer and McGeer, 2007). For instance, tarenflurbil (Flurizan), which is the R-form of flurbiprofen lacking COX-inhibitory activities, was the first γ-secretase modulator to be developed (Eriksen et al., 2003; Kukar et al., 2007). Tarenflurbil showed promising outcomes in early preclinical and clinical trials. However, it failed to show any difference compared to the placebo group in phase III CTs (Green et al., 2009). This failure could have been due to an insufficient amount of tarenflurbil in the brain, as an earlier study (21-day) did not reduce Aβ42 in the plasma or cerebrospinal fluid (CSF) (Galasko et al., 2007).

Recent data suggest that the mechanism by which γ-secretase modulates NSAIDs could be based on binding of the substrate (APP in this case) rather than γ-secretase itself. Binding of the compounds to APP prevents dimerization of APP and shifts the cleavage site such that less toxic Aβ fragments are produced (Richter et al., 2010).

Carriers of mutations in the presenilin gene share heterogeneity among their pathological phenotypes. At the time of its discovery, it was suggested that the presenilin gene undergoes gain-of-function mutations, but since then more than 150 mutations have been identified (PS1 mutation database in ref.). Many of the mutations were found to be reduction-of-function by in vitro assays involving simpler organisms such as C. elegans (Okochi et al., 2000; Wolfe, 2007). Moreover, conditional knockout of PS1 in postnatal forebrain leads to cognitive deficit in the mouse, suggesting that PS1 is required for normal neuronal function in the adults (Yu et al., 2001). This could be a significant factor in the development of γ-seretase inhibitors, and the cause of recent failures in CTs with γ-secretase inhibitors could be due to the disturbance of normal presenilin functions.

BACE inhibitors

Beta-site amyloid precursor protein cleaving enzyme (BACE1) was cloned to measure the enzymatic activity of β-secretase, which is the enzyme responsible for initiating Aβ generation (For review, Cole and Vassar, 2008). Thus, BACE is one of the best drug targets for the therapeutic inhibition of Aβ production. Moreover, it is considered to be a better target than γ-seretase for disease-modifying drugs since the knockout mouse of BACE1 does not produce Aβ and shows only minor behavioral changes (Cai et al., 2001; Roberds et al., 2001). Even though the structure of BACE1 has been solved, the design of potent inhibitors is still problematic since the active site is so large (Hong et al., 2000). CTS-21166 (CoMentis) is the first BACE1 inhibitor tested in phase I CTs. According to information provided by the company, CTS-21166 is safe, well-tolerated and shows dose-related reduction in plasma Aβ 40 (Strobel, 2008c).

LY2811376, another orally available and brainpenetrant inhibitor, showed good tolerance and dose-dependent reduction of plasma Aβ in phase I CTs. However, its trials were terminated due to additional non-clinical toxicology data which was found in the middle of the CTs. Nonetheless, it was clearly demonstrated that BACE1 is a druggable target (Rogers, 2010). TAK-0707, a promising nonpeptidic and lipophilic compound, is non-competitive for substrates and results in reduction of Aβ and cognitive improvement in a mouse AD model (Fukumoto et al., 2010). However, no CT on TAK-0707 is being currently conducted. Other compounds which are derived from peptidomimetics and non-peptides have nano-molar potency in in vitro assays. However, they lack in vivo efficacy data in mouse models. (Hills and Vacca, 2007)

Alternatively, compounds that modulate the activity of β-secretase could be candidates for AD therapeutics. Posiphen is enantiomer of phenserine and is inactive in inhibiting acetylcholine esterase while phenserine has cholinergic activity (see below). Posiphen reduces both Aβ 40 and Aβ 42 in mice and it acts by reducing β-secretase activity as well as that of APP transcription (Lahiri et al., 2007). Recently, recruitment is ongoing for a phase I study in subjects with amnestic mild cognitive impairment (CT 4 in ref.).

The recent discovery that BACE1-knockout mice produce excess sodium channels in their axons, have increased neuronal excitability, and are more susceptible to seizures than normal mice sends a caution to the developers of BACE1 inhibitors (Hu et al., 2010).

Aβ oligomerization inhibitors

Tramiprosate binds to soluble Aβ and prevents formation of amyloid plaques (Gervais et al., 2001). This drug was the first to have been developed based on amyloid cascade theory, reaching latestage development. However, the outcome of its phase III CTs was not conclusive despite promising results in phase II (Wong, 2007). These poor results could have been due to its promotion of tau aggregation or unusually large placebo response rate (Santa-Maria, 2007; Wong, 2007).

Phenserine was developed as an inhibitor of acetylcholine esterase and later demonstrated cognitive improvement in animal models. Use of phenserine reduced the amount of APP by modulating APP translation through interaction with the 5'UTR. Even though moderate success was attained in phase II, the drug failed to show any significant benefit over placebo in phase III trials (Strobel, 2005). ELND005 (formerly known as AZD 103) is a scillo-inositol, one of the 8 possible stereoisomeric forms of inositol. It reduced the accumulation of Aβ oligomers and suppressed memory loss in transgenic mice (Hawkes et al., 2010). Long-term phase II trials using ELND005 did not show significant improvements in cognition even though they showed the effects on CSF Aβ (Fagan, 2010c). PBT2, an anti-fibrillar agent, is a metal-protein-attenuating compound that alters the interaction between Aβ and metals. The phase IIa trial of PBT2 showed the reduction of Aβ 42 in CSF without affecting the plasma biomarkers of AD. Even though no major adverse effects were observed, cognitive improvement was restricted to a part of executive functions (Lannfelt et al., 2008).

Inhibitors of Aβ transport: RAGE inhibitors

The receptor for advanced glycation end products (RAGE) binds Aβ and transports it from plasma to the brain via the blood-brain barrier (Deane et al., 2003). Thus, RAGE has been suggested as a therapeutic target for preventing the accumulation of Aβ in the brain. PF-04494700 (formerly TTP488), the first RAGE inhibitor for AD, was recently developed. Phase II CTs for evaluation of safety and tolerance have been completed. Currently, phase II for efficacy is underway but subjects have not been recruited (CT 5 in ref.).

Degradation of Aβ

Degradation of Aβ could be the most effective strategy for its removal from the brain. There are some proteases that degrade Aβ, as evidenced in vivo using knock-out or over-expressing transgenic mice. Such proteases are insulin-degrading enzymes, including neprilysin and plasmin activator inhibitor-1 (PAI-1) inhibitor. The development of compounds that enhance the degradation of Aβ is still in the exploratory stage. The only compound that has reached CTs is PAZ-417, a PAI-1 inhibitor (Jacobsen et al., 2008). Despite the possibility of bleeding by activation of the plasmin system, there were no severe side effects in any animal model. Two phase I trials have been completed while a third was terminated (CT 6 in ref.).

DRUG DEVELOPMENT FOR TARGETING OF TAU PROTEIN

Even if Aβ is considered to be the major cause of AD pathology, tau could play an important role in AD pathogenesis (Iwatsubo, 2006). Therefore, blocking tau could be an effective therapeutic strategy. Tau is a protein found in the cytoplasm that binds to tubulin for the stabilization of microtubules. During AD, tau is hyperphosphorylated, resulting in NFTs inside neurons, which are toxic to neurons (Iqbal et al., 1994). Kinases that are involved in the hyperphosphorylation of tau are considered as drug targets. However, there are not many drug candidates compared to those of Aβ pathology.

A major therapeutic approach for tau pathology is developing inhibitors of kinases of tau hyperphosphorylation. Several kinases are reported to phosphorylate tau protein, including Glycogen synthase kinase 3β (GSK3β), cyclin-dependent kinase 5 (CDK5), extracellular signal-regulated kinase (ERK), P38 and c-Jun N-terminal kinase (JNK) (Iwatsubo, 2006). Two well known drugs for psychiatric disorders, valproic acid and lithium, inhibit GSK3 and reduce tau phosphorylation. Although valproic acid reached phase III CTs, it failed to show any improvement of neuropsychiatric symptoms in AD patients (Landhuis, 2009a). Lithium also failed to show any change in CSF markers or cognitive improvement in a small trial (Hampel et al., 2009).

Among the several GSK3 inhibitors under development, NP-031112 (NP-12), which is non-competitive to ATP, reduces tau phosphorylation and amyloid deposits in the brain of animal models (Serenó et al., 2009). A phase II trial with this drug has been completed, but the result has not been published.

Alternatively, there are approaches preventing tau aggregation or promoting aggregate disassembly. Methylthioninium chloride (methylene blue, Rember), a widely used dye for protein staining, interferes with tau aggregation and also enhances mitochondrial function. Phase II trials showed slow disease progression, but efficacy and safety still need to be confirmed in phase III CTs (Strobel, 2008b).

Davunetide has been developed as both an intranasally administered peptide of 8 amino acids (AL-108, NAP) and as an intravenous formulation (AL-208). Although the neuroprotective mechanism is not clear, AL108 inhibits tau hyperphosphorylation and protects the brain from Aβ toxicity in animal models (Matsuoka et al., 2007). A phase II study on AL-108 in patients with amnestic mild cognitive impairment showed positive effects on cognitive function (Fagan, 2009a). However, the study was short (12 weeks) and needs to be confirmed by additional studies.

DRUG DEVELOPMENT BASED ON OTHER THEORIES (TABLE 2)

Dimebon, which was developed as a non-selective antihistamine, weakly inhibits acethylcholine esterase (Bachurin et al., 2001). It also inhibits NMDA receptors and voltage-gated calcium channels, but its neuroprotective activity is mainly derived from the enhancement of mitochondrial function (Bachurin et al., 2003). A phase II CT in 2007 showed clear improvement for all outcome measures (Doody et al., 2008). However, the same positive results were not confirmed in phase III trials (Fagan, 2010a).

Since AD patients show reduced insulin signaling in the brain and diabetes increases the risk of developing dementia, there are many approaches to increase insulin in the brain. Recently, a four-month phase II study on intranasal administration of insulin in patients with MCI or early AD showed improved cognition and daily function, with larger phase III trials planned (Landhuis, 2010a). Insulin-like growth factor-1 (IGF-1) is also considered a treatment for neurodegenerative disorders. However, MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, did not benefit AD patients (Sevigny et al., 2008). Recent data from IGF-1 receptor knockout mouse is more confusing: the results suggested that reducing insulin/IGF-1 signaling helps avoid dementia (Fagan, 2009b). A clinical trial to assess the relationship between the levels of IGF-1 system components and cognitive status in patients with AD is underway (CT 7). Drugs that modulate insulin signaling have also been developed. However, rosiglitazone and pioglitazone, both peroxisome proliferator-activated receptor-γ (PPARγ) agonists, did not show significant benefits in patients with mild to moderate AD (Strobel, 2006).

Ginkgo biloba is an herb that is widely used to prevent and treat cognitive decline in aging people. However, CTs conducted for six years (2002~2008) showed that daily doses of standardized ginkgo biloba leaf extract failed to delay the development of AD in 1,545 treated seniors (Dekosky et al., 2008). Huperzine A is a natural alkaloid compound with neuroprotective effects in addition to inhibitory activity of acetylcholine esterase. Despite positive results in phase II CTs, further trials are not ongoing (Wang et al., 2009).

Elevated levels of cholesterol are associated with a risk of AD (Kivipelto and Solomon, 2006), and cholesterol-lowering statins have been suggested to reduce the risk of AD. A transgenic mouse model was used to demonstrate that a high level of cholesterol increases the production of Aβ (Refolo et al., 2000). However, clinical studies on treatment with statins in patients with AD have not produced any beneficial effects so far. Atorvastatin failed to show any benefit in phase III trials (Feldman et al., 2010), and trials with pitavastatin or simvastatin for the prevention and therapy of AD are ongoing (Fagan, 2008b).

Epidemiological data and a neuroinflammation model of AD suggest that NSAID can be effective for the treatment and prevention of AD (Townsend and Pratico, 2005; Tuppo and Arias, 2005). To find the relationship between NSAIDs and AD, four prospective clinical studies were conducted and they showed a reduced risk for AD upon treatment with NSAIDs. However, double blind randomized CTs with placebo groups failed to show that NSAID is an effective treatment for prevention of AD (ADAPT Research Group, 2009). Recent data suggest the prevention should be done in very early stage of AD (Varvel et al., 2009).

Antagonists or agonists of many neurotransmitter receptors have been suggested as drug candidates for AD (Doraiswamy and Xiong, 2006), including SB-742457 (serotonergic, 5-HT6 receptor antagonist; Maher-Edwards et al., 2010), PRX-03140 (5-HT4 agonist, terminated), SR57746A (xaliproden) and Lecozotan SR (5-HT1A receptor antagonist, lack of efficacy), SGS-742 (GABAB-receptor antagonist, unsuccessful), AZD3480 (α4β2-selective neuronal nicotinic receptor agonist; Dunbar et al., 2010), CX717 (AMPA-type glutamate receptor modulator; Hampson et al., 2009) and RO5313534 (MEM 3454, nicotinic α7 receptor agonist; Rezvani et al., 2009).

Phosphodiesterase 4 inhibitors show neuroprotective and neurorengenerative activities in a mouse AD model. MK-0952 completed phase II trials in patients with mild to moderate AD, but the results have not been published and no further clinical trials are going (CT 8). PF-04447943, which is a selective phosphodiesterase 9A inhibitor, was tested for its AD therapeutic efficacy. Phase I was completed, and currently AD patients are recruiting for phase II CTs (Fagan, 2010b).

Women have higher risk than men for AD. It could be due to changes in hormonal regulation after menopause. Modulation of hormones has been suggested as a treatment for AD in women. Raloxifene, a selective estrogen receptor modulator, was tested for the prevention of cognitive decline in postmenopausal women with osteoporosis. High dose (120 mg/day) of raloxifen reduced the risk of mild cognitive impairment (Yaffe et al., 2005; Legault et al., 2009). However, no further development was reported for the drug in the prevention of AD.

Nerve growth factor (NGF) supports survival and fiber outgrowth of basal forebrain cholinergic neurons, and data suggest NGF imbalance activates the production of Aβ, leading to neurodegeneration in AD patients (Cattaneo et al., 2008). There have been many attempts to deliver NGF to basal forebrain cholinergic neurons. However, intracerebroventricular infusion of NGF was interrupted by adverse effects (Eriksdotter et al., 1998). Nonetheless, intracerebral injection of genetically modified cells producing NGF showed an overall lower rate of cognitive decline (Tuszynski et al., 2005). Encapsulated biodelivery of NGF cholinergic basal forebrain neurons was also attempted, and it increases expression of nicotinic receptors and cognitive improvement (Eriksdotte et al., 2010).

Neuroreplacement therapies for neurodegenerative diseases based on stem cells have also been suggested (Sugaya and Merchant, 2008). Other approaches involving vitamin E or omega-3 polyunsaturated fatty acids have also been attempted but the results were inconclusive (Freund-Levi et al., 2006; Bjelakovic et al., 2007). Resveratrol, a phenolic compound derived from grapes and red wine, has neuroprotective effects and has been suggested for AD therapeutics (Sun et al., 2010).

CONCLUSION

AD is a complex, multi-factorial disorder, the mechanism of which has not been fully understood. After considerable success in the drug development of symptomatic AD treatments, the clinical development of new drugs for treatment of AD has resulted only in disappointment. Considering recent failures in clinical trials, more innovative approaches are greatly needed. Approaches based on a single target should be revised because there are several levels of interactions (especially environment) in AD pathogenesis. Therefore, mutli-target therapies should be considered more seriously, with mitochondrial protection and multi-target directed ligands serving as recent examples.

Most of the positive results in AD animal models have not been recapitulated in clinical trials, which implies that the current animal models for AD drug development should be reconsidered. Especially, rodent models might have a more powerful ability to recover brain cells compared to that of human brain (Harrison et al., 2010).

Many studies suggest that certain lifestyle factors could modify the risk of developing AD. Among them, physical exercise may be an effective way to reduce the risk of AD. It has been demonstrated that physical exercise increases the many factors involved in neurogenesis (e.g. BDNF, TrkB, CREB, IGF-1), contribute to Aβ clearance, and improve cognition in animals (Vaynman et al., 2003; Ploughman et al., 2007).

Tables

Table. 1.

Table 1. AD Drug development to target Ab or tau

*MAb: monoclonal antibody, **Clinical trial (s) was failed. See the text.
Table. 2.

Table 2. AD Drug development based on other theories

*The result of CT was inconclusive, **Clinical trial(s) was failed. See the text.

References

  1. Meinert CL, McCaffrey LD, Breitner JC, ADAPT Research Group. Alzheimer's Disease Anti-inflammatory Prevention Trial: design, methods, and baseline results. Alzheimers Dement 2009;5:93-104.
    Pubmed
  2. Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci 2001;939:425-435.
    Pubmed
  3. Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci 2003;993:334-344.
    Pubmed
  4. Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, Robertson BJ, Polson CT, Wang J, Roberts SB, Hendrick JP, Anderson JJ, Loy JK, Denton R, Verdoorn TA, Smith DW, Felsenstein KM. Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharmacol Exp Ther 2005;312:635-643.
    Pubmed
  5. Becker RE, Greig NH. Alzheimer's disease drug development in 2008 and beyond: problems and opportunities. Curr Alzheimer Res 2008;5:346-357.
    Pubmed
  6. Beel AJ, Sanders CR. Substrate specificity of gamma-secretase and other intramembrane proteases. Cellular and Molecular Life Sciences 2008;65:1134-1311.
  7. Best JD, Smith DW, Reilly MA, O'Donnell R, Lewis HD, Ellis S, Wilkie N, Rosahl TW, Laroque PA, Boussiquet-Leroux C, Churcher I, Atack JR, Harrison T, Shearman MS. The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse. J Pharmacol Exp Ther 2007;320:552-558.
    Pubmed
  8. Bettens K, Sleegers K, Van Broeckhoven C. Current status on Alzheimer disease molecular genetics: from past, to present, to future. Hum Mol Genet 2010;19:R4-R11.
    Pubmed
  9. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842-857.
    Pubmed
  10. Brunden KR, Trojanowski JQ, Lee VM. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 2009;8:783-793.
    Pubmed
  11. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001;4:233-234.
    Pubmed
  12. Cattaneo A, Capsoni S, Paoletti F. Towards non invasive nerve growth factor therapies for Alzheimer's disease. J Alzheimers Dis 2008;15:255-283.
    Pubmed
  13. Cole SL, Vassar R. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J Biol Chem 2008;283:29621-29625.
    Pubmed
  14. http://www.clinicaltrials.gov/ct2/show/NCT00904683?term=LY2062430&=1.
  15. http://www.clinicaltrials.gov/ct2/show/NCT00329082?term=LY2062430&rank=3.
  16. http://www.clinicaltrials.gov/ct2/show/NCT00455000?term=04360365&rank=5.
  17. http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01072812.
  18. http://clinicaltrialsfeeds.org/clinical-trials/results/term=PF-04494700.
  19. http://clinicaltrialsfeeds.org/clinical-trials/results/term=paz417.
  20. http://www.clinicaltrials.gov/ct2/show/NCT00647478?term=igf-1+alzheimer&rank=1.
  21. http://www.clinicaltrials.gov/ct2/show/NCT00362024?term =MK-0952&rank=1.
  22. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999;398:518-522.
    Pubmed
  23. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003;9:907-913.
    Pubmed
  24. Dekosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL, Furberg CD, Array. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008;300:2253-2262.
    Pubmed
  25. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci 2002;5:452-457.
    Pubmed
  26. Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jäckel S, Wei X, Buerger K, Höft C, Hemmer B, Möller HJ, Farlow M, Oertel WH, Sommer N, Du Y. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer's disease. Ann Neurol 2002;52:253-256.
    Pubmed
  27. Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, Oertel W. Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence. Drugs 2010;70:513-528.
    Pubmed
  28. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, dimebon investigators. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mildto-moderate Alzheimer's disease: a randomised, doubleblind, placebo-controlled study. Lancet 2008;372:207-215.
    Pubmed
  29. Doraiswamy PM, Xiong GL. Pharmacological strategies for the prevention of Alzheimer's disease. Expert Opin Pharmacother 2006;7:1-10.
    Pubmed
  30. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL, Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Audia JE. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001;76:173-181.
    Pubmed
  31. Dunbar G, Kuchibhatla R, Lee G. A randomized double-blind study comparing 25 and 50 mg TC-1734 (AZD3480) with placebo, in older subjects with age-associated memory impairment. J Psychopharmacol 11 Jun 20102010.
  32. Eriksdotter JM, Linderoth B, Almqvist P, Lind G, Aladellie L, Nordberg A, Kadir A, Jelic V, Seiger A, Wahlberg L. Therapy of Alzheimer's disease with NGF. 11th International Geneva/Springfi eld Symposium on Advances in Alzheimer therapy, 2010, Geneva, Switzerland. Neurobiol Aging 2010;31:S9.
  33. Eriksdotter JM, Nordberg A, Amberla K, Bäckman L, Ebendal T, Meyerson B, Olson L, Seiger, Shigeta M, Theodorsson E, Viitanen M, Winblad B, Wahlund LO. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement Geriatr Cogn Disord 1998;9:246-257.
    Pubmed
  34. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003;112:440-449.
    Pubmed
  35. http://www.alzforum.org/new/detail.asp?id=2530.
  36. http://www.alzforum.org/new/detail.asp?id=2113.
  37. http://www.alzforum.org/new/detail.asp?id=2344.
  38. http://www.alzforum.org/new/detail.asp?id=2387.
  39. http://www.alzforum.org/new/detail.asp?id=2536.
  40. http://www.alzforum.org/new/detail.asp?id=2313.
  41. http://www.alzforum.org/new/detail.asp?id=1859.
  42. http://www.alzforum.org/new/detail.asp?id=2425.
  43. http://www.alzforum.org/new/detail.asp?id=1807.
  44. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, Schwam E, Schindler R, Hey-Hadavi J, DeMicco DA, Breazna A, LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010;74:956-964.
    Pubmed
  45. Freund-Levi Y, Eriksdotter JM, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol 2006;63:1402-1408.
    Pubmed
  46. Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T, Hirode M, Sagayama M, Maeda R, Kawamoto M, Hirai K, Terauchi J, Sakura Y, Kakihana M, Kato K, Iwatsubo T, Miyamoto M. A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci 2010;30:11157-11166.
    Pubmed
  47. Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH. Safety, tolerability, pharmacokinetics, and Abeta levels after shortterm administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 2007;21:292-299.
    Pubmed
  48. Gervais F, Chalifour R, Garceau D, Kong X, Laurin J, Mclaughlin R, Morissette C, Paquette J. Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid 2001;8:28-35.
    Pubmed
  49. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-1562.
    Pubmed
  50. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH, Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease. A randomized controlled trial. JAMA 2009;302:2557-2564.
    Pubmed
  51. Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schonknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009;70:922-931.
    Pubmed
  52. Hampson RE, España RA, Rogers GA, Porrino LJ, Deadwyler SA. Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717. Psychopharmacology (Berl) 2009;202:355-369.
    Pubmed
  53. Harrison FE, Green RJ, Dawes SM, May JM. Vitamin C distribution and retention in the mouse brain. Brain Res 2010;1348:181-186.
    Pubmed
  54. Hawkes CA, Deng LH, Shaw JE, Nitz M, McLaurin J. Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease. Eur J Neurosci 2010;31:203-213.
    Pubmed
  55. Hills ID, Vacca JP. Progress toward a practical BACE-1 inhibitor. Curr Opin Drug Discov Devel 2007;10:383-391.
  56. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000;290:150-153.
    Pubmed
  57. Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, Wilson CG, Yan R. BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 2010;30:8819-8829.
    Pubmed
  58. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM. Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem 2006;281:4292-4299.
    Pubmed
  59. Iqbal K, Alonso AC, Gong CX, Khatoon S, Singh TJ, Grundke-Iqbal I. Mechanism of neurofibrillary degeneration in Alzheimer's disease. Mol Neurobiol 1994;9:119-123.
    Pubmed
  60. Iwatsubo T. Tauopathy: an overview. Neuropathology 2006;26:455-456.
    Pubmed
  61. Jacobsen JS, Comery TA, Martone RL, Elokdah H, Crandall DL, Oganesian A, Aschmies S, Kirksey Y, Gonzales C, Xu J, Zhou H, Atchison K, Wagner E, Zaleska MM, Das I, Arias RL, Bard J, Riddell D, Gardell SJ, Abou-Gharbia M, Robichaud A, Magolda R, Vlasuk GP, Bjornsson T, Reinhart PH, Pangalos MN. Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci 2008;105:8754-8759.
    Pubmed
  62. Kivipelto M, Solomon A. Cholesterol as a risk factor for Alzheimer's disease - epidemiological evidence. Acta Neurol Scand Suppl 2006;185:50-57.
    Pubmed
  63. Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci 2002;22:6331-6335.
    Pubmed
  64. Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, Golde TE, Nicolle MM. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. MC Neurosci 2007;8:54.
  65. Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, Giordano T, Sambamurti K, Greig NH. The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther 2007;320:386-396.
    Pubmed
  66. Landhuis E. AD and epilepsy-lessons from the clinic, animals. Alzheimer Research Forum. Chicago; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=2284
  67. Landhuis E. Intranasal insulin trial claims promise in MCI, AD. Alzheimer Research Forum. Honolulu; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=2518
  68. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=2389.
  69. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=2114.
  70. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW, PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebocontrolled trial. Lancet Neurol 2008;7:779-786.
    Pubmed
  71. Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, Merchant KM. The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 2003;305:864-871.
    Pubmed
  72. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM. Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves. J Biol Chem 2006;281:4292-4299.
    Pubmed
  73. Legault C, Maki PM, Resnick SM, Coker L, Hogan P, Bevers TB, Shumaker SA. Effects of tamoxifen and raloxifene on memory and other cognitive abilities: cognition in the study of tamoxifen and raloxifene. J Clin Oncol 2009;27:5144-5152.
    Pubmed
  74. Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy?. Nat Rev Neurol 2010;6:108-119.
    Pubmed
  75. Maher-Edwards G, Zvartau-Hind M, Hunter AJ, Gold M, Hopton G, Jacobs G, Davy M, Williams P. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Curr Alzheimer Res 2010;7:374-385.
    Pubmed
  76. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol 2010;9:702-716.
    Pubmed
  77. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, Harrison B, Mayer SC, Aschmies S, Gonzales C, Zaleska MM, Riddell DR, Wagner E, Lu P, Sun SC, Sonnenberg-Reines J, Oganesian A, Adkins K, Leach MW, Clarke DW, Huryn D, Abou-Gharbia M, Magolda R, Bard J, Frick G, Raje S, Forlow SB, Balliet C, Burczynski ME, Reinhart PH, Wan HI, Pangalos MN, Jacobsen JS. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 2009;331:598-608.
    Pubmed
  78. Matsuoka Y, Gray AJ, Hirata-Fukae C, Minami SS, Waterhouse EG, Mattson MP, LaFerla FM, Gozes I, Aisen PS. Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage. J Mol Neurosci 2007;31:165-170.
    Pubmed
  79. Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, Atchison K, Chlenov M, Cole DC, Comery T, Diamantidis G, Ellingboe J, Fan K, Galante R, Gonzales C, Ho DM, Hoke ME, Hu Y, Huryn D, Jain U, Jin M, Kremer K, Kubrak D, Lin M, Lu P, Magolda R, Martone R, Moore W, Oganesian A, Pangalos MN, Porte A, Reinhart P, Resnick L, Riddell DR, Sonnenberg-Reines J, Stock JR, Sun SC, Wagner E, Wang T, Woller K, Xu Z, Zaleska MM, Zeldis J, Zhang M, Zhou H, Jacobsen JS. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease. J Med Chem 2008;51:7348-7351.
    Pubmed
  80. McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging 2007;28:639-647.
    Pubmed
  81. Okochi M, Eimer S, Bottcher A, Baumeister R, Romig H, Walter J, Capell A, Steiner H, Haass C. A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells. J Biol Chem 2000;275:40925-40932.
    Pubmed
  82. Ploughman M, Granter-Button S, Chernenko G, Attwood Z, Tucker BA, Mearow KM, Corbett D. Exercise intensity influences the temporal profile of growth factors involved in neuronal plasticity following focal ischemia. Brain Res 2007;1150:207-216.
    Pubmed
  83. Prince M, Jackson J. World Alzheimer disease. . London: Alzheimer's Disease International, 2009; 2009. p. 25-46.
  84. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 2000;7:321-331.
    Pubmed
  85. Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED. Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:269-275.
    Pubmed
  86. Richter L, Munter LM, Ness J, Hildebrand PW, Dasari M, Unterreitmeier S, Bulic B, Beyermann M, Gust R, Reif B, Weggen S, Langosch D, Multhaup G. Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Abeta and interfere with amyloid precursor protein (APP) transmembrane dimerization. PNAS 2010;107:14597-14602.
    Pubmed
  87. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genet 2001;10:1317-1324.
    Pubmed
  88. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=2537.
  89. Santa-Maria I, Hernández F, Del Rio J, Moreno FJ, Avila J. Tramiprosate, a drug of potential interest for the treatment of Alzheimer's disease, promotes an abnormal aggregation of tau. Mol Neurodegener 2007;2:17.
    Pubmed
  90. Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T. A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis 2009;35:359-367.
    Pubmed
  91. Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML. Growth hormone secretagogue MK-677: no clinical effect on AD progression in randomized trial. Neurology 2008;71:1702-1708.
    Pubmed
  92. Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow MR, Paul SM, Demattos RB. Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 2010;33:67-73.
    Pubmed
  93. Strobel G. Bapineuzumab's phase 2-was the data better than the spin?. Alzheimer Research Forum. Chicago; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=1894
  94. Strobel G. Out of the blue-a Tau-based treatment for AD?. Alzheimer Research Forum. Chicago; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=1892
  95. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=2093.
  96. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=1257.
  97. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=1790.
  98. Strobel G. Highs and lows of the insulin connection. Alzheimer Research Forum. Madrid; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=1458
  99. Strobel G. γ-secretase inhibitor survived phase 2. Alzheimer Research Forum. Washington; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=2536
  100. Strobel G. GAMMA-secretase inhibitor survived phase 2, moving to 3. Alzheimer Research Forum. Washington; [accessed Sept. 3, 2010]. , http://www.alzforum.org/new/detail.asp?id=1607
  101. Sugaya K, Merchant S. How to approach Alzheimer's disease therapy using stem cell technologies. J Alzheimers Dis 2008;15:241-254.
    Pubmed
  102. Sun AY, Wang Q, Simonyi A, Sun GY. Resveratrol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol 2010;41:375-383.
    Pubmed
  103. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003;422:438-441.
    Pubmed
  104. Townsend KP, Praticò D. Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J 2005;19:1592-1601.
    Pubmed
  105. Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 2005;37:289-305.
    Pubmed
  106. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, Conner J. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005;11:551-555.
    Pubmed
  107. Varvel NH, Bhaskar K, Kounnas MZ, Wagner SL, Yang Y, Lamb BT, Herrup K. NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest 2009;119:3692-3702.
    Pubmed
  108. Vaynman S, Ying Z, Gomez-Pinilla F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 2003;122:647-657.
    Pubmed
  109. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis. J Neural Transm 2009;116:457-465.
    Pubmed
  110. Wolfe MS. Inhibition and modulation of gammasecretase for Alzheimer's disease. Neurotherapeutics 2008;5:391-398.
    Pubmed
  111. Wolfe MS. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40.Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 2007;8:136-140.
    Pubmed
  112. Alzheimer Research Forum http://www.alzforum.org/new/detail.asp?id=1647.
  113. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004;279:12876-12882.
    Pubmed
  114. Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry 2005;162:683-690.
    Pubmed
  115. Yu H, Saura CA, Choi SY, Sun LD, Yang X, Handler M, Kawarabayashi T, Younkin L, Fedeles B, Wilson MA, Younkin S, Kandel ER, Kirkwood A, Shen J. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 2001;31:713-726.
    Pubmed

Print ISSN : 1226-2560

Online ISSN : 2093-8144

© 2019. Experimental Neurobiology: the official journal of the Korean Society for Brain and Neural Sciences & the Korean Society for Neurodegenerative Disease.