Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer"s disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.

Noves perspectives en el diagnòstic del deteriorament cognitiu lleu i la malaltia de l'Alzheimer

Els criteris per al diagnòstic clínic de la malaltia d’Alzheimer es van establir el 1984 pel National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) i la Alzheimer’s Disease and Related Disorders Association (ADRDA). D’aplicació continuada fins a l’actualitat, aquests criteris estan quedant obsolets i per tant des de diversos àmbits s’ha abogat per una revisió profunda dels mateixos. Tres grups d’experts formats per reconeguts especialistes del National Institute on Aging (NIA) i la Alzheimer’s Association proposen un conjunt de recomanacions per modificar aquests criteris en l’àmbit de la investigació clínica. Dues diferències remarcables s’inclouen en aquests nous criteris: la incorporació de biomarcadors i la formalització de diferents estadis de la malaltia d’Alzheimer. D’aquesta manera, el deteriorament cognitiu lleu s’incorpora al procés diagnòstic com un estadi més de la patologia. Tanmateix, aquests criteris es troben en revisió i, de moment sols son aplicables en l’àmbit de recerca per tal d’arribar a un consens definitiu que permeti la modificació definitiva dels criteris clínics universals a aplicar. En aquest article es presenten els principals avenços en la investigació referents a la malaltia d’Alzheimer i al Deteriorament Cognitiu lleu per tal d’emmarcar els nous criteris de recerca.

Un estudi relaciona l'Alzheimer amb l'evolució del cervell humà

La recerca indica que la plasticitat del cervell té un doble vessant: és bàsica per a la intel·ligència humana, però també té efectes col·laterals, com la possible demència

Personalidad premórbida y factores de riesgo en la enfermedad de Alzheimer

El presente artículo hace un repaso de los principales estudios respecto a los factores de riesgo para la enfermedad de Alzheimer, priorizando los factores psicosociales y especialmente los que se refieren a la personalidad premórbida. Entre los factores psicosociales de riesgo, aparecen como los más destacados un bajo nivel educativo y una actividad-relación social restringida. Necesidad de protección, tutelaje y dependencia de otras personas, relación social e interpersonal restringida e introversión, son los elementos de riesgo más relevantes para la personalidad premórbida. Los factores que aparecen en los estudios mencionados tienen relación con la hipótesis de trabajo de la investigación que se desarrolla actualmente, acerca de los perfiles de riesgo en la personalidad premórbida. Esta hipótesis los sitúa en el campo de lo emocional y de la relación interpersonal: fragilidad de la identidad personal y sostenimiento del yo a través de una relación simbiótica con el otro.

A common BACE1 polymorphism is a risk factor for sporadic Creutzfeldt-Jakob disease

The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer"s disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer"s and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players

Diagnosis of Alzheimer’s Disease from EEG by Means of Synchrony Measures in Optimized Frequency Bands

Several clinical studies have reported that EEG synchrony is affected by Alzheimer’s disease (AD). In this paper a frequency band analysis of AD EEG signals is presented, with the aim of improving the diagnosis of AD using EEG signals. In this paper, multiple synchrony measures are assessed through statistical tests (Mann–Whitney U test), including correlation, phase synchrony and Granger causality measures. Moreover, linear discriminant analysis (LDA) is conducted with those synchrony measures as features. For the data set at hand, the frequency range (5-6Hz) yields the best accuracy for diagnosing AD, which lies within the classical theta band (4-8Hz). The corresponding classification error is 4.88% for directed transfer function (DTF) Granger causality measure. Interestingly, results show that EEG of AD patients is more synchronous than in healthy subjects within the optimized range 5-6Hz, which is in sharp contrast with the loss of synchrony in AD EEG reported in many earlier studies. This new finding may provide new insights about the neurophysiology of AD. Additional testing on larger AD datasets is required to verify the effectiveness of the proposed approach.

Methylglyoxal Produced by Amyloid- Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer’s Disease

Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.

Improving the Quality of EEG Data in Patients With Alzheimers Disease Using ICA

Does Independent Component Analysis (ICA) denature EEG signals? We applied ICA to two groups of subjects (mild Alzheimer patients and control subjects). The aim of this study was to examine whether or not the ICA method can reduce both group di®erences and within-subject variability. We found that ICA diminished Leave-One- Out root mean square error (RMSE) of validation (from 0.32 to 0.28), indicative of the reduction of group di®erence. More interestingly, ICA reduced the inter-subject variability within each group (¾ = 2:54 in the ± range before ICA, ¾ = 1:56 after, Bartlett p = 0.046 after Bonfer- roni correction). Additionally, we present a method to limit the impact of human error (' 13:8%, with 75.6% inter-cleaner agreement) during ICA cleaning, and reduce human bias. These ¯ndings suggests the novel usefulness of ICA in clinical EEG in Alzheimer's disease for reduction of subject variability.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

A Theta-Band EEG Based Index for Early Diagnosis of Alzheimer’s Disease

Despite recent advances, early diagnosis of Alzheimer’s disease (AD) from electroencephalography (EEG) remains a difficult task. In this paper, we offer an added measure through which such early diagnoses can potentially be improved. One feature that has been used for discriminative classification is changes in EEG synchrony. So far, only the decrease of synchrony in the higher frequencies has been deeply analyzed. In this paper, we investigate the increase of synchrony found in narrow frequency ranges within the θ band. This particular increase of synchrony is used with the well-known decrease of synchrony in the band to enhance detectable differences between AD patients and healthy subjects. We propose a new synchrony ratio that maximizes the differences between two populations. The ratio is tested using two different data sets, one of them containing mild cognitive impairment patients and healthy subjects, and another one, containing mild AD patients and healthy subjects. The results presented in this paper show that classification rate is improved, and the statistical difference between AD patients and healthy subjects is increased using the proposed ratio.

MemoryCon : Una aplicació d'Android per a potenciar la memòria dels malalts d'Alzheimer

This Degree Project is the development of an application for mobile devices with Android operating system. It is based on a generic manual with exercises for Alzheimer patients. The aim of the manual -and therefore, of the video game- is simply to be helpful in stimulating cognitive abilities of patients, ie players.

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.