Traditional Chinese medicinal herbs as potential AChE inhibitors for anti-Alzheimer’s disease: A review

Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting 25 million people worldwide, and cholinergic hypothesis is considered as an important hypotheses in the processes of improving cognitive function and recognition skills in recent years. For the long-term treatment of AD, traditional Chinese medicine are particularly suitable for drug discovery. In this review, we sum up six traditional Chinese medicinal herbs concerned with development of AChEIs, including Herba Epimedii, Coptis Chinensis Franch, Rhizoma Curcumae Longae, Green tea, Ganoderma, Panax Ginseng. The listed compounds based on these herbs are belonging to six classes Flavonoids, Alkaloids, Ketones, Polyphenols, Terpenoid and Saponins, respectively. These compounds could be very promising agents in the search for potent anti-Alzheimer’s drugs.     

Periodontitis and Alzheimer’s disease: oral systemic link still on the rise?

doi: 10.1111/j.1741‐2358.2012.00660.x Periodontitis and Alzheimer’s disease: Oral systemic link still on the rise? Over the past few years, there has been a rapid rise in the older segments of the world population, which has brought along with it a major health concern: dementia. Alzheimer’s disease, considered to be the most common cause of dementia, has become a prospect feared by the elderly. Inflammation of the brain is strongly implicated in Alzheimer’s disease which could be enhanced by systemic inflammation. Periodontitis being a chronic inflammatory condition, which can cause systemic inflammation, the question is whether chronic periodontitis can initiate or hasten the rate of progression of Alzheimer’s disease in susceptible individuals. In this article, the authors outline the proposed oral systemic link between periodontitis and Alzheimer’s disease.     

Design,synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer’s disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC₅₀ 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.     

A synthetic fragment 60–70 of the receptor for advanced glycation end products exhibits a therapeutic effect in an animal model of Alzheimer’s disease

Six synthetic peptides overlapping a fragment 60–76 of the receptor for advanced glycation end products (RAGE) were studied on a protective effect on spatial memory of animals in the experimental model of Alzheimer’s disease. It was shown that only a peptide corresponding to the fragment 60–70 of RAGE exhibits a therapeutic activity. Intranasal administration of this peptide into bulbectomized mice, which develop neurodegenerative features of the Alzheimer type, completely protects animal memory. Thus, it was found that the N-terminal region (60–70) within the peptide sequence 60–76 of RAGE is responsible for the revealed protective effect. The synthetic peptide RAGE-(60–70) could be the basis for the development of a new drug for the treatment of Alzheimer’s disease.     

Alzheimer’s Disease is an Important Risk Factor of Fractures: a Meta-analysis of Cohort Studies

The risk of fracture in individuals with Alzheimer’s disease had not been fully quantified. A systematic review and meta-analysis of cohort studies was performed to estimate the impact of Alzheimer’s disease on risk of fractures. Pubmed and Embase were searched for eligible cohort studies assessing the association between Alzheimer’s disease and risk of fractures. The overall relative risks (RRs) with 95% CIs were calculated using a random-effects model to evaluate the association. Six cohort studies with a total of 137,986 participants were included into the meta-analysis. Meta-analysis of a total of six studies showed that Alzheimer’s disease was significantly associated with two-fold increased risk of fractures (RR?=?2.18, 95 % CI 1.64–2.90, P?<?0.001; I ²?=?91.4 %). Meta-regression analysis showed that type of fractures was a source of heterogeneity (P?=?0.003). Meta-analysis of five studies on hip fracture showed that Alzheimer’s disease was significantly associated with 2.5-fold increased risk of hip fracture (RR?=?2.52, 95 % CI 2.26–2.81, P?<?0.001; I ²?=?25.2 %). There was no risk of publication bias observed in the funnel plot. There is strong evidence that Alzheimer’s disease is a risk factor of hip fracture.     

Design,synthesis and evaluation of curcumin-based fluorescent probes to detect Aβ fibrils

Amyloid β fibrillation is an early event in Alzheimer’s disease, so its detection is important to understand its roles in Alzheimer’s disease. Curcumin, which has poor water solubility, has been reported to have many pharmacological activities including potent anti-amyloid β fibril activity in Alzheimer’s disease. In this study, we found that curcumin analogues with the fluorescence property instead of non-inhibition of amyloid β fibrils. The development of new curcumin analogue, Me-CUR (9), as fluorescent switchable probe to detect amyloid β fibrils is described. Me-CUR (9) shows excellent fluorescence, especially higher than ThT (4), in the presence of amyloid β fibrils. These results suggest that Me-CUR (9) can become a useful in vitro amyloid fluorescence sensor for diagnosis of Alzheimer’s disease.     

Preferential inhibition of acetylcholinesterase molecular forms in rat brain

The effect of eight different acetylcholinesterase inhibitors (AChEIs) on the activity of acetylcholinesterase (AChE) molecular forms was investigated. Aqueous-soluble and detergent-soluble AChE molecular forms were separated from rat brain homogenate by sucrose density sedimentation. The bulk of soluble AChE corresponds to globular tetrameric (G₄), and monomeric (G₁) forms. Heptylphysostigmine (HEP) and diisopropylfluorophosphate were more selective for the G₁ than for the G₄ form in aqueous-soluble extract. Neostigmine showed slightly more selectivity for the G₁ form both in aqueous- and detergent-soluble extracts. Other drugs such as physostigmine, echothiophate, BW284C51, tetrahydroaminoacridine, and metrifonate inhibited both aqueous- and detergent-soluble AChE molecular forms with similar potency. Inhibition of aqueous-soluble AChE by HEP was highly competitive with Triton X-100 in a gradient, indicating that HEP may bind to a detergent-sensitive non-catalytic site of AChE. These results suggest a differential sensitivity among AChE molecular forms to inhibition by drugs through an allosteric mechanism. The application of these properties in developing AChEIs for treatment of Alzheimer disease is considered.Special issue dedicated to Dr. Morris H. Aprison.     

Amyloid-beta peptide decreases expression and function of glutamate transporters in nervous system cells

Glutamate is an essential excitatory neurotransmitter that regulates brain functions, and its activity is tightly regulated by glutamate transporters. Excess glutamate in the synaptic cleft and dysfunction of excitatory amino acid transporters have been shown to be involved in development of Alzheimer’s disease, but the precise regulatory mechanism is poorly understood. Using a D-[³H]-aspartic acid uptake assay, we found that Aβ_1-42 oligomers impaired glutamate uptake in astrocytes and neurons. In astrocytes, this process was accompanied by reduced expression of GLT-1 and GLAST as detected by Western blot and immunocytofluorescence. However, mRNA levels of EAATs detected by qPCR in astrocytes and neurons were not altered, which suggests that this process is post-translational. Co-localization analysis using immunocytofluorescence showed that ubiquitylation of GLT-1 significantly increased. Therefore, we hypothesized that Aβ_1-42 oligomers-induced endocytosis of astrocytic GLT-1 may be involved in ubiquitylation. In addition, Aβ_1-42 oligomers enhanced secretion of IL-1β, TNF-α, and IL-6 into culture supernatant, which may be correlated with an inflammatory response and altered EAATs expression or function in Alzheimer’s disease. These findings support the idea that dysregulation of the glutamatergic system may play a significant role in pathogenesis of Alzheimer’s disease. Furthermore, enhancing expression or function of EAATs in astrocytes and neurons might be a new therapeutic approach in treatment of Alzheimer’s disease.     

The DRD2 <Emphasis Type="Italic">Taq1A A1</Emphasis> Allele May Magnify the Risk of Alzheimer’s in Aging African-Americans

Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer’s; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer’s disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer’s in aging African-Americans. Research linking this high risk for Alzheimer’s in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.     

Protective Effect of Paeoniflorin on Aβ25–35-Induced SH-SY5Y Cell Injury by Preventing Mitochondrial Dysfunction

Alzheimer’s disease (AD) is a major neurodegenerative brain disorder affecting about 14 million people worldwide. Aβ-induced cell injury is a crucial cause of neuronal loss in AD, thus the suppression of which might be useful for the treatment of this disease. In this study, we aimed to evaluate the effect of paeoniflorin (PF), a monoterpene glycoside isolated from aqueous extract of Radix Paeoniae Alba, on Aβ_25–35-induced cytotoxicity in SH-SY5Y cells. The results showed PF could attenuate or restore the viability loss, apoptotic increase, and ROS production induced by Aβ_25–35 in SH-SY5Y cells. In addition, PF strikingly inhibited Aβ_25–35-induced mitochondrial dysfunction, which includes decreased mitochondrial membrane potential, increased Bax/Bcl-2 ratio, cytochrome c release and activity of caspase-3 and caspase-9. Therefore, our study provided the first experimental evidence that PF could modulate ROS production and apoptotic mitochondrial pathway in model of neuron injury in vitro and which might provide new insights into its application toward Alzheimer’s disease therapy.     

Catechol-O-Methyltransferase Val158Met Polymorphism on Striatum Structural Covariance Networks in Alzheimer’s Disease

The catechol-O-methyltransferase enzyme metabolizes dopamine in the prefrontal axis, and its genetic polymorphism (rs4680; Val158Met) is a known determinant of dopamine signaling. In this study, we investigated the possible structural covariance networks that may be modulated by this functional polymorphism in patients with Alzheimer’s disease. Structural covariance networks were constructed by 3D T1 magnetic resonance imaging. The patients were divided into two groups: Met-carriers (n = 91) and Val-homozygotes (n = 101). Seed-based analysis was performed focusing on triple-network models and six striatal networks. Neurobehavioral scores served as the major outcome factors. The role of seed or peak cluster volumes, or a covariance strength showing Met-carriers > Val-homozygotes were tested for the effect on dopamine. Clinically, the Met-carriers had higher mental manipulation and hallucination scores than the Val-homozygotes. The volume-score correlations suggested the significance of the putaminal seed in the Met-carriers and caudate seed in the Val-homozygotes. Only the dorsal-rostral and dorsal-caudal putamen interconnected peak clusters showed covariance strength interactions (Met-carriers > Val-homozygotes), and the peak clusters also correlated with the neurobehavioral scores. Although the triple-network model is important for a diagnosis of Alzheimer’s disease, our results validated the role of the dorsal-putaminal-anchored network by the catechol-O-methyltransferase Val158Met polymorphism in predicting the severity of cognitive and behavior in subjects with Alzheimer’s disease.     

Effects of Ferrofluid and Phytoalexin Spirobrassinin on Thioflavin-T-Based Fluorescence in Cerebrospinal Fluid of the Elderly and Multiple Sclerosis Patients

It is well known that misfolded peptides/proteins can play a role in processes of normal ageing and in the pathogenesis of many diseases including Alzheimer’s disease. Previously, we evaluated samples of cerebrospinal fluid from patients with Alzheimer’s disease and multiple sclerosis by means of thioflavin-T-based fluorescence. We observed attenuated effects of magnetite nanoparticles operated via anti-aggregation actions on peptides/proteins from patients with Alzheimer’s disease but not from those with multiple sclerosis when compared to age-related controls. In this study, we have evaluated the in vitro effects of anti-aggregation operating ferrofluid and phytoalexin spirobrassinin in the cerebrospinal fluid of patients with multiple sclerosis and Alzheimer’s disease. We have found significant differences in native fluorescence (λ excitation = 440 nm, λ emission = 485 nm) of samples among particular groups (young controls < multiple sclerosis, Alzheimer’s disease < old controls). Differences among groups were observed also in thioflavin-T-based fluorescence (young controls = multiple sclerosis < Alzheimer’s disease < old controls) and the most marked change from native to thioflavin-T-based fluorescence was found in young controls (28–40 years old people). Both ferrofluid and spirobrassinin evoked drops in thioflavin-T-based fluorescence; however, ferrofluid was more efficient in old controls (54–75 years old people) and spirobrassinin in multiple sclerosis patients, both compared to young controls. The results are discussed especially in relation to aggregated peptides/proteins and liposoluble fluorescent products of lipid peroxidation. Based on the significant effect of spirobrassinin in vitro, we suggest that spirobrassinin may be of therapeutic value in multiple sclerosis.     

Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography

Late-onset Alzheimer’s disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer’s disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD’s genetic etiology. Subsets of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid–calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.     

New approaches to the immunotherapy of Alzheimer’s disease with the synthetic fragments of α7 subunit of the acetylcholine receptor

The effect of immunization with the synthetic fragments of the α7 subunit of the acetylcholine nicotine receptor on the spatial memory of mice subjected to olfactory bulbectomy, which causes the development of the neurodegenerative disease of Alzheimer’s type, was studied. NMRI mice were immunized with the KLH conjugates of two peptide fragments of the N-terminal fragment of the α7 subunit extracellular fragment, subjected to olfactory bulbectomy to cause the development of the neurodegenerative disease of Alzheimer’s type, and then the state of the spatial memory was evaluated. It was shown that 20% of bulbectomized mice immunized with N-terminal 1–23 fragment exhibited good spatial memory after training. Immunization with the peptide construct (159–167)-(179–188) consisting of two hydrophilic exposed regions of α7-subunit induced good spatial memory in 50% of bulbectomized mice, while in the control group, which received only KLH, none of animals were learned. Thus, the development of immunotherapy with peptide (159–167)-(179–188) seems to be a promising approach to prophylaxis and treatment of Alzheimer’s disease.     

The Role of Arginine–Nitric Oxide Pathway in Patients with Alzheimer Disease

There is a reciprocal regulation of arginase and nitric oxide synthase in l-arginine-metabolizing pathways. There are various evidences of the role of nitric oxide in several neuropsychiatric disorders including Alzheimer’s disease. However, there is no study that has investigated the role of arginase as an important part of the arginine regulatory system affecting nitric oxide synthase activity in Alzheimer’s disease. This study aims to investigate arginase, manganese (a cofactor of arginase), and total nitrite levels (a metabolite of NO) and their relationship to the arginine–NO pathway in patients with Alzheimer’s disease. Arginase activities, Mn, and total nitrite levels were measured in plasma from 47 patients with Alzheimer’s disease and 43 healthy control subjects. Plasma arginase activities and manganese were found to be significantly lower and total nitrite level higher in patients with Alzheimer’s disease compared with controls. Our results suggest that the arginine–NO pathway is involved in the pathogenesis of Alzheimer’s disease.     

Toepassing van stemmingsvragenlijsten bij ouderen met alzheimerdementie (met of zonder taalstoornis) en hun informanten

Introduction

Alzheimer’s Dementia (AD) may be associated with symptoms of depression. In AD, problems of language expression or understanding will arise sooner or later. The aim of this study was to determine whether elderly persons with AD, with or without a language disorder, experience difficulties understanding and answering mood related questions. In addition to this, it was our object to test the validity of the answers of nurses as informants, on the mood of an elderly client.

Methods

53 elderly persons, living in care homes, and their nurses, took part in the study. 25 participants had been diagnosed with Alzheimer’s disease, 28 participants had no cognitive impairment. Language skills were tested using the SAN-test (Stichting Afasie Nederland) and subtests of the Aachen Aphasia Test (AAT). Mood was assessed with the Beck Depression Inventory-second edition (BDI-II-NL) and the Geriatric Depression Scale (GDS-30).

Results

There were no significant differences in scores on the mood related questionnaires between participants without cognitive impairment and participants with Alzheimer’s disease, with or without a language disorder. The correlation between self- and informant-rating was very limited. In general, nurses reported more depressive symptoms than the elderly persons did themselves. Disparities between self- and informant-ratings varied from informant scores overestimating low self-ratings of depression to informant scores underestimating high self-ratings.

Conclusion

Alzheimer’s disease, whether or not it is complicated by a language disorder, does not disturb the normal score distribution on either test (BDI or GDS). This means that elderly persons with Alzheimer’s disease are capable of adequately answering questions related to their own mood. However, considerable discrepancies were found between observer- and self-ratings of emotional wellbeing. Therefore it is important to not only take into account the information of an informant when testing for depression, but also the elderly person’s own assessment of their mood.

     

Identification of Risk Pathways and Functional Modules for Coronary Artery Disease Based on Genome-wide SNP Data

Coronary artery disease(CAD) is a complex human disease, involving multiple genes and their nonlinear interactions, which often act in a modular fashion. Genome-wide single nucleotide polymorphism(SNP) profiling provides an effective technique to unravel these underlying genetic interplays or their functional involvements for CAD. This study aimed to identify the susceptible pathways and modules for CAD based on SNP omics. First, the Wellcome Trust Case Control Consortium(WTCCC) SNP datasets of CAD and control samples were used to assess the jointeffect of multiple genetic variants at the pathway level, using logistic kernel machine regression model. Then, an expanded genetic network was constructed by integrating statistical gene–gene interactions involved in these susceptible pathways with their protein–protein interaction(PPI)knowledge. Finally, risk functional modules were identified by decomposition of the network. Of 276 KEGG pathways analyzed, 6 pathways were found to have a significant effect on CAD. Other than glycerolipid metabolism, glycosaminoglycan biosynthesis, and cardiac muscle contraction pathways, three pathways related to other diseases were also revealed, including Alzheimer's disease, non-alcoholic fatty liver disease, and Huntington's disease. A genetic epistatic network of 95 genes was further constructed using the abovementioned integrative approach. Of 10 functional modules derived from the network, 6 have been annotated to phospholipase C activity and cell adhesion molecule binding, which also have known functional involvement in Alzheimer's disease.These findings indicate an overlap of the underlying molecular mechanisms between CAD and Alzheimer's disease, thus providing new insights into the molecular basis for CAD and its molecular relationships with other diseases.     

Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease

All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C₆–C₇ N-alkyl chains for cholinesterase inhibition.     

阿尔茨海默症基因研究态势分析

阿尔茨海默症是一种起病隐匿的进行性发展的神经系统退行性疾病。随着全球老龄化日趋严重,阿尔茨海默症严重威胁人民的生命健康与生活质量。阿尔茨海默症成因复杂,治疗阿尔茨海默症仍然是重要的医学难题。通过对Web of Science核心合集中收录的阿尔茨海默症基因研究相关的文献,利用文献计量的方法,进行研究趋势、研究人员、研究机构、国家和研究热点等方面进行态势分析,为相关领域的研究人员提供重要的参考。     

Neuronal Autophagy: Self-eating or Self-cannibalism in Alzheimer’s Disease

Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer’s disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, β-amyloid peptide (plaques) and τ-protein (tangles). In Alzheimer’s disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer’s disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer’s disease brains. τ-protein has been found to control the stability of microtubules, however, phosphorylation of τ-protein or an increase in the total level of τ-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer’s disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for β-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of β-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for β-amyloid peptide aggregation and accumulation in Alzheimer’s disease. However, the key role of autophagy in Alzheimer’s disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, β-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer’s disease. In this review we present the recent evidence linking autophagy to Alzheimer’s disease and the role of autophagic regulation in the development of full-blown Alzheimer’s disease.