Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β- and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β- and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

/pdf/amyloid-beta-structure-biology-and-structure-based-3y96h59gd4.pdf

Amyloid beta: structure, biology and structure-based therapeutic development

Alzheimer's disease is the most common cause of dementia in elderly people. Research into Alzheimer's disease therapy has been at least partly successful in terms of developing symptomatic treatments, but has also had several failures in terms of developing disease-modifying therapies. These successes and failures have led to debate about the potential deficiencies in our understanding of the pathogenesis of Alzheimer's disease and potential pitfalls in diagnosis, choice of therapeutic targets, development of drug candidates, and design of clinical trials. Many clinical and experimental studies are ongoing, but we need to acknowledge that a single cure for Alzheimer's disease is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information on pieces of the complex Alzheimer's disease puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Several promising randomised controlled trials are ongoing, and the increased collaboration between pharmaceutical companies, basic researchers, and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of Alzheimer's disease.

/pdf/alzheimer-s-disease-clinical-trials-and-drug-development-46wp4j0jf2.pdf

Alzheimer's disease: clinical trials and drug development

Vaccination has made an enormous contribution to global health. Two major infections, smallpox and rinderpest, have been eradicated. Global coverage of vaccination against many important infectious diseases of childhood has been enhanced dramatically since the creation of WHO's Expanded Programme of Immunization in 1974 and of the Global Alliance for Vaccination and Immunization in 2000. Polio has almost been eradicated and success in controlling measles makes this infection another potential target for eradication. Despite these successes, approximately 6.6 million children still die each year and about a half of these deaths are caused by infections, including pneumonia and diarrhoea, which could be prevented by vaccination. Enhanced deployment of recently developed pneumococcal conjugate and rotavirus vaccines should, therefore, result in a further decline in childhood mortality. Development of vaccines against more complex infections, such as malaria, tuberculosis and HIV, has been challenging and achievements so far have been modest. Final success against these infections may require combination vaccinations, each component stimulating a different arm of the immune system. In the longer term, vaccines are likely to be used to prevent or modulate the course of some non-infectious diseases. Progress has already been made with therapeutic cancer vaccines and future potential targets include addiction, diabetes, hypertension and Alzheimer's disease.

https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2013.0433

The contribution of vaccination to global health: past, present and future

Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15–20 years before clinical symptoms occur, mainly owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease. Potential disease-modifying therapies for Alzheimer disease have mostly targeted brain accumulation of amyloid-β, but this approach has yet to provide substantial clinical benefits. The authors consider the reasons for this failure and suggest alternative strategies, including modification of risk factors.

A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease.

Therapeutics of Alzheimer's disease: Past, present and future.

Summary Background Immunotherapy targeting the amyloid β (Aβ) peptide is a potential strategy to slow the progression of Alzheimer's disease We aimed to assess the safety and tolerability of CAD106, a novel active Aβ immunotherapy for patients with Alzheimer's disease, designed to induce N-terminal Aβ-specific antibodies without an Aβ-specific T-cell response Methods We did a phase 1, double-blind, placebo-controlled, 52-week study in two centres in Sweden Participants, aged 50–80 years, with mild-to-moderate Alzheimer's disease were entered into one of two cohorts according to time of study entry and then randomly allocated (by use of a computer-generated randomisation sequence) to receive either CAD106 or placebo (4:1; cohort one received CAD106 50 μg or placebo, cohort two received CAD106 150 μg or placebo) Each patient received three subcutaneous injections All patients, caregivers, and investigators were masked to treatment allocation throughout the study Primary objectives were to assess the safety and tolerability of CAD106 and to identify the Aβ-specific antibody response Safety assessment was done by recording of all adverse events, assessment of MRI scans, physical and neurological examinations, vital signs, electrocardiography, electroencephalography, and laboratory analysis of blood and CSF Patients with Aβ-IgG serum titres higher than 16 units at least once during the study were classified as responders This study is registered with ClinicalTrialsgov, number NCT00411580 Findings Between August, 2005, and March, 2007, we randomly allocated 31 patients into cohort one (24 patients to CAD106 treatment and seven to placebo) and 27 patients into cohort two (22 patients to CAD106 treatment and five to placebo) 56 of 58 patients reported adverse events In cohort one, nasopharyngitis was the most commonly reported adverse event (10 of 24 CAD106-treated patients) In cohort two, injection site erythema was the most commonly reported adverse event (14 of 22 CAD106-treated patients) Overall, nine patients reported serious adverse events—none was thought to be related to the study drug We recorded no clinical or subclinical cases of meningoencephalitis 16 of 24 (67%) CAD106-treated patients in cohort one and 18 of 22 (82%) in cohort two developed Aβ antibody response meeting pre-specified responder threshold One of 12 placebo-treated patients (8%) had Aβ-IgG concentrations that qualified them as a responder Interpretation Our findings suggest that CAD106 has a favourable safety profile and acceptable antibody response in patients with Alzheimer's disease Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106 Funding Novartis Pharma AG

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(12)70140-0.pdf

Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study

Liquid chromatography−mass spectrometry (LC−MS) is a common method for profiling biological samples in metabolomics. However, LC−MS data of metabolomic studies are often affected by high noise levels, retention time shifts, and high variability in signal intensities. With a new chip-based nanoelectrospray source it becomes possible to directly infuse complex biological samples such as plasma without any chromatographic separation beforehand. In combination with highly diluted samples and long data acquisition times, the parallel analysis of hundreds of compounds is now possible. In a proof-of-concept study, 10 human plasma samples from females and males were analyzed with the intention to separate the two groups by their different metabolomes. The reproducibility was so high that statistical analysis of the data could be performed without prior normalization. Two groups of female and male samples were separated by a supervised machine learning algorithm, principal component analysis, and hierarchical clus...

Controlled Protein Precipitation in Combination with Chip-Based Nanospray Infusion Mass Spectrometry. An Approach for Metabolomics Profiling of Plasma

Methods are disclosed for fast and accurate readout of kidney toxicity before it occurs and before it is demonstrated by histopathology examination. Ultimately this approach shall allow earlier compound selection. The twelve genes identified, namely Calbindin-D28k, KIM-1, OPN, EGF, Clusterin, VEGF, OAT-K1, Aldolase A, Aldolase B, Podocin, Alpha-2u and C4, were grouped and ultimately can be assessed in the form of a kit using PCR, a high throughput technology, in order to characterize and rank new compounds according to their anticipated general kidney toxicity. Also disclosed are methods for identifying agents useful in the treatment of kidney disease, methods for monitoring the efficacy of a treatment for kidney disease and kidney-specific vectors including the sequences of the disclosed genes, and a method for identifying a candidate gene associated with a biological process including kidney function.

Marker genes for determining renal toxicity

Results of the first-in-man study with the active Aβ Immunotherapy CAD106 in Alzheimer patients

Optimization of the treatment regimen with active Aß immunotherapy CAD106 in alzheimer patients

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