Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 12, Number 33, 2006

Contents


Alzheimer Drug Design Based on the Amyloid Hypothesis
Executive Editors: D. Muñoz-Torrero and P. Camps


Editorial Pp. 4281-4282


Vaccine Development for Alzheimer’s Disease Pp. 4283-4293
K.A. DaSilva, I. Aubert and J. McLaurin
[Abstract]


Views on Amyloid Hypothesis and Secretase Inhibitors for Treating Alzheimer’s Disease: Progress and Problems Pp. 4295-4312
J-T. Nguyen, A. Yamani and Y. Kiso
[Abstract]


Gamma-Secretase as a Pharmacological Target in Alzheimer Disease Research: When, Why and How? Pp. 4313-4335
C. Ziani-Cherif, B. Mostefa-Kara and F.Z. Brixi-Gormat
[Abstract]


Selective Modulation of Aβ 42 Production: Non-Steroidal Anti Inflammatory Drugs (NSAIDs) and Beyond Pp. 4337-4355
S. Leuchtenberger, D. Beher and S. Weggen
[Abstract]


The Development of Preventives and Therapeutics for Alzheimer’s Disease that Inhibit the Formation of β-Amyloid Fibrils (fAβ), as Well as Destabilize Preformed fAβ Pp. 4357-4375
K. Ono, H. Naiki and M. Yamada
[Abstract]


Targeting Beta-Amyloid Pathogenesis Through Acetylcholinesterase Inhibitors Pp. 4377-4387
A. Castro and A. Martinez
[Abstract]


Molecular and Biochemical Features in Alzheimer’s Disease Pp. 4389-4408
M. Pallàs and A. Camins
[Abstract]




Abstracts
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Editorial

Alzheimer Drug Design Based on the Amyloid Hypothesis

Alzheimer’s disease (AD), one of the current major health problems, is already approaching epidemic proportions, affecting millions of people worldwide, while an effective curative or preventive therapy still remains elusive. Ever since the discovery of the direct relationship between most cholinergic markers in the central nervous system and the cognitive and functional decline experienced by AD patients, as well as the subsequent establishment of the cholinergic hypothesis of AD thirty years ago, cholinomimetic agents, and, in particular, acetylcholinesterase inhibitors (AChEIs) have assumed a prominent position in our reduced therapeutic arsenal for the treatment of this disease. However, these treatments have always been regarded as merely symptomatic. Consequently, there is an urgent need for alternative therapies targeting the underlying mechanisms of the disease, thus allowing the interruption or reversal of AD progression.

After the sequenciation of the β-amyloid peptide (Aβ) and the recognition of this species as the primary component of the senile plaques present in the brains of AD patients twenty years ago, this peptide emerged as the ideal therapeutic target, directly related to the pathogenesis of the disease. Even if the primary cause of AD still remains speculative, during the last decade, mounting evidence point toward the misprocessing of the amyloid precursor protein (APP) and the increase in formation and aggregation of the resulting neurotoxic Aβ peptide as the major and early event in the pathogenesis of AD. The generally recognized central role of Aβ formation and aggregation in the etiology of AD has made the amyloid hypothesis, the rationale basis for the current most promising therapeutic approaches to AD, which are called to be the first therapeutic options for AD in virtue of their disease-modifying potential. Unfortunately, the clinical trials implying the most advanced of the amyloid-directed therapies, such as Aβ vaccination (AN1792), were recently cancelled by safety issues, after having shown very interesting beneficial effects on both plaque burden and cognitive decline. While safer alternative immunization approaches are being actively pursued, other amyloid-directed therapies are beginning to enter human trials.

Several lines of evidence point out a connection between both the amyloid and the cholinergic hypotheses of AD, which seem not to be neither independent nor mutually exclusive. APP processing, and consequently, Aβ formation, as well as Aβ aggregation seem to be under cholinergic control, which has renewed the interest for cholinomimetic agents, especially for AChEIs, as disease-modifying amyloid- and cholinergic-directed drug candidates.

In this issue, the current status of vaccination against AD is discussed, as well as other potentially disease-modifying therapies which specifically target Aβ production, aggregation or neurotoxicity.

In Chapter 1, Dr. McLaurin and colleagues [1] discuss the benefits and drawbacks of the firstly developed Aβ immunization therapies and present several novel approaches to immunotherapy, re-designed from the initial vaccines, which hold promise for safer and effective human use. The enzymes responsible for Aβ synthesis from APP, β- and γ-secretases, have emerged as very attractive pharmacological targets. In Chapters 2 and 3, promising anti-Alzheimer drug candidates with the pharmacological profile of β- and γ-secretase inhibitors are presented. Thus, Dr. Kiso and colleagues [2] provide an insightful overview of the different strategies aimed at decreasing Aβ production through disruption of the pathological APP processing, with a particular emphasis on the rational design of peptidomimetic and non-peptidomimetic β-secretase inhibitors, while Dr. Ziani-Cherif and colleagues [3] have provided a comprehensive review focused on the design of the different structural classes of γ-secretase inhibitors, including a discussion on the potential problematic of these compounds due to the promiscuity of this protease to cleave a broad amount of physiologically important proteins such as Notch. Dr. Weggen and colleagues [4] present an exciting review of non-steroidal anti-inflammatory drugs and related compounds which, through direct modulation of γ-secretase, display preferential lowering activity for the most neurotoxic form of Aβ (Aβ42), without eliciting toxic effects derived from the processing of the Notch receptor and other γ-secretase substrates. In Chapter 5, Dr. Yamada and colleagues [5] present several classes of compounds which interfere with the amyloid cascade after the synthesis of Aβ, by inhibition of the formation of Aβ fibrils and destabilization of the preformed fibrils as key molecules for the development of preventives and therapeutics for AD. The enzyme acetylcholinesterase (AChE) accelerates Aβ deposition, thus playing an important role during an early step in the development of the senile plaques, and, consequently, in the pathogenesis of AD. The interference of AChE upstream in the cascade of neurodegeneration of AD and the identification of the recognition site of Aβ within AChE has spurred the design of particular classes of AChEIs as disease-modifying amyloid- and cholinergic-directed drug candidates, which are reviewed by Drs. Martinez and Castro [6] in Chapter 6. Finally, Drs. Pallàs and Camins [7] provide an overview of the different molecular mechanisms underlying the pathogenesis of AD, highlighting the potential mechanisms involved in Aβ-induced neuronal cell death, whose understanding enables the design of alternative preventive or disease-modifying anti-Alzheimer drug candidates.

Although to date, clinically validated treatments for AD remain confined to symptomatic interventions derived from the cholinergic hypothesis, the pace of discovery on therapies derived from the amyloid-hipothesis of AD allow to hold promise that a preventive or curative treatment of AD will soon be available, thus fulfiling one of the most important unmet needs in the modern medicine.

References

[1] DaSilva KA, Aubert I, McLaurin J. Vaccine Development for Alzheimer's Disease. Curr Pharm Design 2006; 12(33): 4283-4293.

[2] Nguyen JT, Yamani A, Kiso Y. Views on Amyloid Hypothesis and Secretase Inhibitors for Treating Alzheimer’s Disease: Progress and Problems. Curr Pharm Design 2006; 12(33): 4295-4312.

[3] Ziani-Cherif C, Mostefa-Kara B, Brixi-Gormat FZ. Gamma-Secretase as a Pharmacological Target in Alzheimer Disease Research. When, Why and How?. Curr Pharm Design 2006; 12(33): 4313-4335.

[4] Leuchtenberger S, Beher D, Weggen S. Selective Modulation of Aβ 42 Production: Non-steroidal Anti-inflammatory Drugs (NSAIDs) and Beyond. Curr Pharm Design 2006; 12(33): 4337-4355.

[5] Ono K, Naiki H, Yamada M. The Development of Preventives and Therapeutics for Alzheimer’s Disease that Inhibit the Formation of β-Amyloid Fibrils (fAβ), as well as Destabilize Preformed fAβ. Curr Pharm Design 2006; 12(33): 4357-4375.

[6] Castro A, Martinez A. Targeting Beta-Amyloid Pathogenesis Through Acetylcholinesterase Inhibitors. Curr Pharm Design 2006; 12(33): 4377-4387.

[7] Pallàs M, Camins A. Molecular and Biochemical Features in Alzheimer’s Disease. Curr Pharm Design 2006; 12(33): 4389-4408.

Diego Muñoz-Torrero
Professor
Laboratori de Química Farmacèutica
Facultat de Farmàcia
Universitat de Barcelona
Av. Diagonal, 643
08028-Barcelona
Spain

Pelayo Camps
Professor
Laboratori de Química Farmacèutica
Facultat de Farmàcia
Universitat de Barcelona
Av. Diagonal, 643
08028-Barcelona
Spain


[Back to top]
Vaccine Development for Alzheimer’s Disease
K.A. DaSilva, I. Aubert and J. McLaurin

Alzheimer’s disease (AD) is the most common cause of age-related cognitive decline. Both active and passive immunization paradigms have illustrated the potential to prevent and reverse established AD pathology in transgenic and non-transgenic animal models of AD. Follow-up studies have shown that changes in amyloid burden observed with immunization could rescue cognitive deficits in both young and aged mice. Despite the success of immunotherapy in animal models, clinical trials were halted early. It has become clear that more preclinical work was needed before initiating trials, as most of the adverse events observed in patients could have been predicted using animal models. Despite these setbacks, clinical trials have demonstrated the utility of amyloid-β (Aβ) vaccination in reducing amyloid pathology and potentially reducing cognitive decline. Several novel approaches to immunotherapy, including modified immunogens, adjuvants and modes of administration have been designed, which hold promise for human testing. Clinical trials using a safer vaccine, which is potent enough to elicit a robust antibody response in the absence of encephalitis may prove effective in mitigating progressive neurodegeneration seen in AD. If so, Aβ vaccination could supplant current symptomatic treatment and represent one of the first therapeutic options for AD based on the amyloid cascade hypothesis.


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Views on Amyloid Hypothesis and Secretase Inhibitors for Treating Alzheimer’s Disease: Progress and Problems
J-T. Nguyen, A. Yamani and Y. Kiso

Alzheimer’s disease is a form of sporadic, age-related dementia. According to the “amyloid hypothesis”, the processing of β-amyloid precursor protein (APP) leads to the formation of senile plaque aggregates which subsequently congest normal neurological functions. Currently, prophylaxis is testimonial, while treatment relies mainly on symptomatic relief. This review emphasizes the importance of disrupting the pathological processing of APP via α-secretase activators, β- and γ-secretase inhibitors, and compounds that bind APP. The style of writing should appeal to those with strong interests in medicinal chemistry with an equal balance of medicine and chemistry.


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Gamma-Secretase as a Pharmacological Target in Alzheimer Disease Research: When, Why and How?
C. Ziani-Cherif, B. Mostefa-Kara and F.Z. Brixi-Gormat

Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the form of senile plaques as well as neurofibrillary tangles (NFTs) in the brain. In the amyloidogenic pathway, the amyloid-β precursor protein (APP) is cleaved by β-secretase first, followed by γ-secretase cleavage producing therefore Aβ. This review summarizes the recent findings in the AD field and focuses on the different γ-secretase inhibitors that have been developed as a therapeutic approach toward AD.


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Selective Modulation of Aβ 42 Production: Non-Steroidal Anti Inflammatory Drugs (NSAIDs) and Beyond
S. Leuchtenberger, D. Beher and S. Weggen

The amyloid-β (Aβ) peptides and in particular the longer, highly amyloidogenic isoform Aβ 42 are believed by many to be the central disease-causing agents in Alzheimer’s disease (AD). Consequently, academic and pharmaceutical laboratories have focused on elucidating the mechanisms of Aβ production and developing strategies to diminish Aβ formation for treatment or prevention of AD. The most substantial advances have been made with respect to inhibitors of the γ-secretase enzyme, which catalyzes the final step in the generation of Aβ from the amyloid precursor protein (APP). Highly potent γ-secretase inhibitors which suppress production of all Aβ peptides are available today. However, due to the promiscuous substrate specificity of γ-secretase and its essential role in the NOTCH signaling pathway overt mechanism-based toxicity has been observed in preclinical studies of γ-secretase inhibitors. For that reason, specific blockage of Aβ 42 production might be preferable over non-discriminatory γ-secretase inhibition but small molecule inhibitors of Aβ 42 production have remained elusive until recently. This has changed with the discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen possess preferential Aβ 42-lowering activity. These compounds seem to offer a window of modulation where Aβ 42 production is potently inhibited whereas processing of the NOTCH receptor and other γ-secretase substrates remains unaffected. The Aβ 42-lowering activity of NSAIDs is not related to inhibition of cyclooxygenases and can be dissociated from the anti-inflammatory properties of this class of drugs. Ongoing efforts concentrate on uncovering the mechanism of action and improving potency and brain permeability of Aβ 42-lowering compounds. Hopes are high that in the near future this will lead to the development of clinically viable compounds which selectively target Aβ 42 as a key molecule in the pathogenesis of AD.


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The Development of Preventives and Therapeutics for Alzheimer’s Disease that Inhibit the Formation of β-Amyloid Fibrils (fAβ), as Well as Destabilize Preformed fAβ
K. Ono, H. Naiki and M. Yamada

Neuritic plaques composed mainly of amyloid β-protein (Aβ) in the brain are an early and invariant neuropathological feature of Alzheimer’s disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of Aβ deposition in the brain. In this article, the recent development of the molecules that inhibit the formation of β-amyloid fibrils (fAβ), as well as destabilize preformed fAβ is reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation, extension of fAβ, as well as destabilize preformed fAβ at pH 7.5 at 37°C in vitro. In cell culture experiments, destabilized fAβ were suggested to be less toxic than intact fAβ. In transgenic mice model study, some coumpounds such as curcumin and nicotine have also been reported to reduce plaque burden in vivo. Although the mechanisms by which these compounds inhibit fAβ formation from Aβ, and destabilize preformed fAβ are still unclear, they could be key molecules for the development of preventives and therapeutics for AD.


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Targeting Beta-Amyloid Pathogenesis Through Acetylcholinesterase Inhibitors
A. Castro and A. Martinez

Although the hallmarks of neurodegeneration in Alzheimer's brains are well known, one of the current difficulties is related to the lack of solid evidence about the ultimate factors that give rise to the pathogenesis of this disease, creating a great challenge for the definition of efficient treatments for Alzheimer's disease (AD). Current therapeutic option for AD patients is the use of acetylcholinesterase (AChE) inhibitors, which gives only a symptomatic relief. However, recent studies show a long-lasting effect in a certain percentage of patients. In fact, there is accumulating evidence that an AChE has secondary non-cholinergic functions including the processing and deposition of β-amyloid (Aβ). AChE could play a role in the Aβ metabolism and during an early step in the development of the senile plaque, as revealed by the finding that AChE accelerates Aβ deposition. Considering the non-classical AChE functions, their relationships with AD hallmarks, and the putative role of peripheral anionic site in all these functions, the dual binding site AChE inhibitors may acquire importance for AD treatment. On the other hand, the interference of AChE inhibitors with Aβ processing is not a general rule for this class of compounds with the involvement of other features such as chemical structure and/or genetic regulation. This review highlights the collection of several compounds with an outstanding profile against AChE-induced amyloid aggregation and potent AChE inhibitory activity, indicating the possibility of targeting Aβ through the inhibition of AChE and reveals the emergence of a new generation of AChE inhibitors aiming to be excellent candidate drugs for the future cure of Alzheimer´s disease.


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Molecular and Biochemical Features in Alzheimer’s Disease
M. Pallàs and A. Camins

The purpose of this review is to discuss the pathophysiological pathways involved in pathogenesis of Alzheimer's disease pointing out current and future pharmacological targets. Alzheimer's disease is one of the most important neurodegenerative disorders in the developed world together with Parkinson’s disease. Although this disease was described almost a century ago, the molecular mechanisms that lead to the development of the neuronal pathology are not clear at the moment. Furthermore, although enormous efforts have been done, an efficient treatment for the disease does not exist yet because the mechanism of neuronal cell death is unknown. In the present work we discuss, in depth, the potential mechanisms involved in apoptosis and neuronal death in Alzheimer’s disease. The biology, structure and physiological properties of β-amyloid peptide and related proteases (secretases) are discussed, as well as existing therapeutics and future strategies for the treatment of Alzheimer’s disease. Inhibition of production of amyloid peptides by secretase inhibitors has been suggested as one of the most rational and specific therapeutic approaches. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration, or blockade of NMDA receptors could constitute suitable therapeutic strategies for Alzheimer’s disease. Finally, a multiple therapy with antioxidants, cell cycle inhibitors and other drugs modulating APP processing could be, in the future, a suitable strategy in order to delay Alzheimer’s disease progression.