Inhibition of neurofibrillary degeneration: a promising approach to Alzheimer's disease and other tauopathies

Neurofibrillary degeneration (ND) is both a pivotal and a primary lesion of Alzheimer disease (AD) and related tauopathies. To date in all known tauopathics including AD, the neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau, and the number of these lesions directly correlates to the degree of dementia in the affected individuals. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAPI and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF/SF. Missense mutations in tau that cosegregate with the disease in inherited cases of frontotemporal dementia make it a more favorable substrate for hyperphosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. The abnormal hyperphosphorylation of tau and neurofibrillary degeneration may be inhibited by increasing the activity of PP-2A, inhibiting the activity of one or more tau kinases or by the sequestration of normal tau by the abnormally hyperphosphorylated tau. A great advantage of developing therapeutic drugs to inhibit neurofibrillary degeneration is that the efficacy of these drugs can be monitored by assaying the CSF levels of phosphotau and total tau, both of which are elevated in AD. Thus, the development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to AD and related tauopathies.     

Development of anti-Abeta vaccination as a promising therapy for Alzheimer's disease

Alzheimer's disease is the most common cause of dementia characterized by progressive neurodegeneration. Recently, a vaccine therapy for Alzheimer's disease was developed as a curative treatment. Although clinical trials of active vaccination for Alzheimer's disease were halted due to the development of meningoencephalitis in some patients, the clinical and pathological findings of treated patients suggest that the vaccine therapy is effective. Hence, newly designed vaccines are being invented to control excessive T-cell immune reactions after the human clinical trial. In this article, we will review conventional vaccine therapies and newly developed vaccine therapies, mainly DNA vaccines, for possible clinical application in the near future.     

Development of BACE1 inhibitors for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The production and accumulation of beta-amyloid peptides (Abeta) from the beta-amyloid precursor protein (APP) are believed to play a key role in the onset and progression of AD. BACE1 (beta-site APP cleaving enzyme 1) is the protease responsible for the N-terminal cleavage of APP leading to the production of Abeta peptides and the development of BACE1 inhibitors as potential therapeutic agents for AD has generated tremendous interests from both academia and the pharmaceutical industry. A wide variety of BACE1 inhibitors have been reported, several of which have demonstrated highly promising efficacy in animal models of AD. This review focuses on recent disclosures of BACE1 inhibitors in the patent and scientific literature, covering the period from approximately May 2004 to November 2005.     

Beta-secretase (BACE) as a drug target for Alzheimer's disease

Evidence suggests that the beta-amyloid peptide (Abeta) is central to the pathophysiology of Alzheimer's Disease (AD). Amyloid plaques, primarily composed of Abeta, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early on-set familial AD (FAD) by increasing synthesis of the toxic Abeta42 peptide. Given the strong association between Abeta and AD, therapeutic strategies to lower the concentration of Abeta in the brain should prove beneficial for the treatment of AD. Abeta is a proteolytic product of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called beta- and gamma-secretase, cleave APP to generate the Abeta peptide. For over a decade, the molecular identities of these proteases were unknown. Recently, the gamma-secretase has been tentatively identified as the presenilin proteins, PS1 and PS2, and the beta-secretase has been shown to be the novel transmembrane aspartic protease, beta-site APP Cleaving Enzyme 1 (BACE1; also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also identified, and the two BACE enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the beta-secretase, and as the key enzyme that initiates the formation of Abeta, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes our current understanding of BACE1 post-translational processing and intracellular trafficking. Finally, recent studies of BACE1 knockout mice, the BACE1 X-ray structure, and implications for BACE1 drug development will be discussed.     

Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush

Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced Abeta aggregation and display antioxidant properties, emerging as lead candidates for treating AD.     

The potential for BACE1 inhibitors in the treatment of Alzheimer's disease

Alzheimer's disease (AD) is a debilitating neurodegenerative disease of the elderly characterized by the loss of memory and other cognitive functions. Currently marketed drugs for the treatment of this disease only offer symptomatic relief, and, consequently, there is a large unmet clinical need for disease-modifying therapies for the treatment of AD. Substantial research efforts are focused on inhibiting the proteases involved in the generation of the amyloidogenic beta-amyloid (A beta) peptide. One of these key proteases, beta-secretase, was identified as a novel transmembrane aspartic protease and named BACE1. Due to its pivotal role in A beta production, many pharmaceutical companies are actively pursuing the challenging task of developing BACE1 inhibitors for evaluation in the clinic.     

The inhibition of gamma-secretase as a therapeutic approach to Alzheimer's disease

Alzheimer's disease is a dementing neurodegenerative disorder for which there is no effective treatment at present. Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta contribute to the etiology of Alzheimer's disease. gamma-Secretase is the pivotal enzyme in generating the C terminus of Abeta which determines its aggregability and speed of deposition. Drugs that regulate the production of Abeta by inhibiting gamma-secretase activity could provide an effective therapy for Alzheimer's disease, although recent studies suggest that gamma-secretase plays important roles in cellular signaling. This review focuses on studies of the gamma-secretase biology and provides the direction for developing effective and selective gamma-secretase inhibitors as drugs for the treatment of Alzheimer's disease.     

Inhaled phage therapy: a promising and challenging approach to treat bacterial respiratory infections

Introduction: Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site.

Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation.

Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy’s clinical positioning in the antimicrobial arsenal against RTIs.     

Metal ions, Alzheimer's disease and chelation therapy

In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.     

Inhibition of cathepsin K--a novel approach to antiresorptive therapy

Cathepsin K is a cysteine protease enzyme with high and specific expression in osteoclasts, the cells responsible for resorbing bone. Its discovery and the numerous lines of evidence that support a specialised role for cathepsin K in bone resorption are discussed. Inhibition of this enzyme would be anticipated to prevent bone resorption, and be of potential utility in diseases involving excess bone loss, such as osteoporosis. The pharmaceutical companies known to be involved in developing inhibitors of cathepsin K, and their progress to date, are described.     

Alteration of ceramide 1-O-functionalization as a promising approach for cancer therapy

Sphingolipids, which are complex lipidic components of the cell membranes, lie in a key position to modulate the pathways of trans-membrane signaling and allow the cell to adapt to environmental stresses. In malignancies, reduced production of some sphingolipid species able to induce apoptosis such as ceramide and conversely, increased levels of some other metabolites involved in tumor progression and drug resistance of cancer cells, are often described. In this context, the discovery of new chemical entities able to specifically modify ceramide metabolism should offer novel pharmacological tools in cancer therapy. The review dedicates particular attention to the enzymes that modify ceramide at the C1-OH position generating other biologically important sphingolipids in cancer, such as sphingomyelin, ceramide-1-phosphate or glucosylceramide. Findings reported in the literature leading to the development of new chemical entities specifically designed to achieve the above goals have been collected and are discussed. The effects of enzyme inhibitors of sphingomyelin synthase, ceramide kinase and glucosylceramide synthase on cancer cell proliferation, sensitivity to chemotherapeutics, induction of apoptosis or growth of xenografts are presented.     

Post-Translational Modifications of BACE1 in Alzheimer's Disease

Beta-Amyloid Cleaving Enzyme1 (BACE1) is a monospecific enzyme for the key rate-limiting step in the synthesis of beta-amyloid(Aβ) from cleavage of amyloid precursor protein (APP), to form senile plaques and causes cognitive dysfunction in Alzheimer''s disease (AD). Post-translation modifications of BACE1, such as acetylation, glycosylation, palmitoylation, phosphorylation, play a crucial role in the trafficking and maturation process of BACE1. The study of BACE1 is of great importance not only for understanding the formation of toxic Aβ but also for the development of an effective therapeutic target for the treatment of AD. This paper review recent advances in the studies about BACE1, with focuses being paid to the relationship of Aβ, BACE1 with post- translational regulation of BACE1. In addition, we specially reviewed studies about the compounds that can be used to affect post-translational regulation of BACE1 or regulate BACE1 in the literature, which can be used for subsequent research on whether BACE1 is a post-translationally modified drug.     

Combination therapy for Alzheimer's disease

Alzheimer's disease (AD) is a progressive, degenerative brain disease. The mainstay of current management of patients with AD involves drugs that provide symptomatic therapy. Two classes of medications have been approved by the US FDA for the treatment of AD: the cholinesterase inhibitors (ChEIs), which include galantamine and rivastigmine (both approved for use in mild to moderate AD) and donepezil (approved for use in mild to severe AD); and the non-competitive NMDA receptor antagonist memantine (approved for use in moderate to severe AD). The European and Asian regulatory bodies have also approved ChEIs as monotherapy in mild to moderate AD. Future research directions are mostly focusing on disease modification and prevention. This review covers key studies of the efficacy, safety and tolerability of combination therapy in AD, defined as a combination of the NMDA receptor antagonist memantine with any of the ChEIs (donepezil, galantamine or rivastigmine) for the treatment of AD. Relevant studies were identified via a PubMed search. This review shows that combination therapy for AD seems to be safe, well tolerated and may represent the current gold standard for treatment of moderate to severe AD and possibly mild to moderate AD as well.     

Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti-cancer therapy

Introduction: Enhancement of glucose metabolism and repression of oxidative phosphorylation followed by the Warburg effect is the common hallmark of cancer cells. Hexokinase II (HKII) plays a dual role – first, HKII up-regulation results in increased glycolysis rates. Second, association of VDAC and HKII contributes to inhibition of apoptosis through repression of the formation of mitochondrial permeability transition pores.

Areas covered: In this review, the role of HKII in evasion of apoptosis, aspects of HKII expression regulation, novel approaches targeting HKII and VDAC–HKII complexes and their application areas are discussed.

Expert opinion: The dual role of HKII in cancer cells makes it an attractive target for anti-cancer therapy. Several agents, either synthetic or plant-derived, that target hexokinase and induce VDAC–HK complex dissociation have been identified to date. Targeting hexokinase, HK–VDAC complexes as well as other glycolytic proteins not only improves the efficacy of commonly used drugs. The most prominent benefit of this approach is the ability to overcome drug resistance, for example, to cisplatin or sorafenib. In some cases, it could create an insurmountable challenge for selection of appropriate therapy. Future studies and trials should address the issue of how to transfer these approaches into clinical practice.     

Diflomotecan,a promising homocamptothecin for cancer therapy

Diflomotecan, a 10,11-difluoro-homocamptothecin, represents a new promising class of topoisomerase I inhibitors with enhanced plasma stability and superior preclinical anti-tumour activity as compared to the established camptothecins, irinotecan and topotecan. Diflomotecan was the first homocamptothecin to enter clinical studies. Phase I data are summarized for both the intravenous and oral schedules. The toxicity is primarily haematological while no severe gastrointestinal toxicity has been observed in contrast to other topoisomerase I inhibitors. Diflomotecan has a high oral bioavailability (72 – 95%) and the oral day 1 – 5 every 3 weeks regimen is recommended for Phase II testing because it is relatively well tolerated, convenient and mimics protracted exposure. This review summarizes the developments and innovations in the topoisomerase I inhibitor field with an emphasis on diflomotecan.     

Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: a promising approach in anti-retroviral therapy

Although 25 compounds are currently licensed as anti-HIV drugs, the development of multidrug-resistant viruses, as well as their severe side effects, compromise their efficacy and limit treatment options. The search for new targets in order to cure AIDS has revealed that the inhibition of some protein-protein interactions in the HIV life cycle may provide an important new approach to fight this disease. The interaction between HIV-1 integrase (IN) and Lens Epithelium-Derived Growth Factor (LEDGF/p75) has increasingly gained attention as a valuable target for a novel anti-retroviral strategy. This article reviews the discovery and development of molecules capable of interrupting the LEDGF/p75-IN interaction reported to date.     

RNA interference as a tool for Alzheimer's disease therapy

RNA interference is a biological process that controls gene silencing in all living cells. Targeting the RNA interference system represents a novel therapeutic strategy able to intercede with multiple disease-related genes and to target many neurodegenerative diseases. Recently, the design of small interfering RNA-selective compounds has become more straightforward because of the significant progress made in predictive modeling for new therapeutic approaches. Although in vivo delivery of RNA interference remains a significant obstacle, new data show that RNAi blocks gene function in vivo, suggesting a potential therapeutic approach for humans. Some groups have demonstrated the efficacy of RNAi therapy in Alzheimer's disease. Results, based on animal models, show a down-regulation of the amyloid precursor protein and a consequent reduction of the amyloid-beta peptide accumulation in the brain or the inactivation of beta-secretase (BACE1). Indeed, lentiviral vectors expressing siRNAs targeting BACE1 reduce amyloid production and the neurodegenerative and behavioural deficit in APP transgenic mice. This review highlights recent advances in RNA research and focuses on strengths and weaknesses of RNAi compounds in Alzheimer's disease.