Prevention and Treatment of Alzheimer's Disease by Traditional Chinese Medicine via Regulating ROS： A Review / 中国实验方剂学杂志

The pathological mechanism of Alzheimer's disease （AD） is complex， and there are many hypotheses. The mainstream theory is the amyloid-beta protein （Aβ） and Tau protein phosphorylation. Oxidative stress （OS） is a bridge between other hypotheses and mechanisms and plays a key role in many hypotheses. Therefore， the treatment of OS in AD （ADOS） is beneficial in alleviating disease progression. Reactive oxygen species （ROS） is a kind of antioxidant and a kind of oxidation products， with Aβ and Tau protein interactions， activating microglia and astrocytes， triggering inflammation and mitochondrial dysfunction， leading to the deterioration of the environment in the brain， and accelerating the development of disease. ROS， as a signal messenger inducing OS， is widely involved in the progression of AD and may be a new target for the progression of AD. Traditional Chinese medicine （TCM） monomers and compounds play an increasingly important role in the prevention and treatment of AD. Recent studies have found that the effective prevention and treatment of AD by TCM is closely related to the regulation of ROS. There are many studies on the mechanism of TCM in the treatment of AD via regulating ROS， but there is a lack of systematic review. By analyzing and summarizing the literature in China and abroad in recent years， this paper reviewed the generation and physiology of ROS， the mechanism of action of AD， and the prevention of AD by TCM via regulating ROS through relevant ways， so as to provide references for the research on the regulation of ROS by TCM and provide new targets and new methods for the prevention and treatment of AD.

Molecular Mechanism Study of β-amyloid Aggregation Inhibition by Transthyretin / 生物化学与生物物理进展

ObjectiveIt was reported that the transthyretin (TTR) has a neuroprotective effect on Alzheimer’s disease (AD), which is manifested by the ability of TTR to inhibit the pathological aggregation of amyloid beta protein (Aβ). In this work, we investigated the mechanism of the interactions between TTR and Aβ at the molecular level to reveal the neuroprotective effect of TTR on AD. MethodsProtein-protein docking was used to explore the models of interaction between different structural forms of TTR and Aβ, and molecular dynamics simulation was further applied to investigate the dynamic process of the interaction between the two. ResultsBoth TTR tetramer and monomer can interact with Aβ monomer, and the thyroxine-binding channel of TTR tetramer is the main binding site of Aβ monomer. In addition, the EF helix and EF loop of TTR tetramer were also able to bind Aβ monomer. When the TTR tetramer dissociates, the hydrophobic site of the internal TTR monomer is exposed, which has a strong affinity for Aβ monomer. For the interaction between Aβ aggregates and TTR, a higher degree of aggregation can be formed between TTR monomer and Aβ aggregates due to the β-sheet-rich property of TTR monomer and Aβ aggregates, which may therefore reduce the cytotoxicity of Aβ aggregates. ConclusionBoth TTR tetramer and monomer can inhibit Aβ aggregation by “sequestering” Aβ monomer, while TTR monomer can reduce the cytotoxicity of Aβ aggregates by forming large co-aggregation with Aβ aggregates. This work can provide an important theoretical basis for the design and discovery of anti-AD drugs based on the neuroprotective effects of TTR.

Relationship between serum indexes,pathogenetic condition and prognosis in patients with acute ischemic stroke / 天津医药

Objective To discuss the relationship between serum lipoprotein-associated phospholipase A2(Lp-PLA2),low-density lipoprotein(LDL),amyloid beta 1-42(Aβ1-42)and soluble intercellular adhesion molecule-1(sICAM-1)levels,the National Institutes of Health Stroke Scale(NIHSS)score and prognosis in patients with acute ischemic stroke(AIS).Methods A total of 106 patients with AIS who underwent intravenous thrombolysis(the thrombolysis group),30 AIS patients without thrombolysis(the non-thrombolysis group)and 95 healthy individuals(the control group)were included in the study.The thrombolysis group was divided into the recanalization group(n=41)and the non-recanalization group(n=65)according to whether the vein was recanalized after thrombolysis.Patients were divided into the mild group(n=45),the moderate group(n=36)and the severe group(n=25)based on the NIHSS score.They were divided into the good prognosis group(n=65)and the poor prognosis group(n=41)based on the modified Rankin Scale(mRS)score.Serum levels of four indexes in different groups were compared.Their relationship with the NIHSS score and the prognosis was analyzed.Results The vein recanalization rate in 106 patients with thrombolysis was 38.68%(41/106).Serum Lp-PLA2,LDL,Aβ1-42 and sICAM-1 levels were lower in the recanalization group than those in the non-canalization group(P＜0.05).Serum Lp-PLA2,LDL,Aβ1-42 and sICAM-1 levels increased successively in the control group,the thrombolysis group and the non-thrombolysis group(P＜0.05).The 4 serum indexes increased with the aggravation of disease condition,and were positively correlated with NIHSS score(P＜0.05).High serum levels of Lp-PLA2,LDL,Aβ1-42 and sICAM-1 were risk factors for poor prognosis of patients with thrombolysis(P＜0.05).The area under the curve(AUC)and specificity of the combination of 4 serum indexes for predicting poor prognosis of patients with thrombolysis were higher than those of prediction with single index(P＜0.05).Conclusion The expression levels of serum Lp-PLA2,LDL,Aβ1-42 and sICAM-1 in patients with AIS are high.They can be used as important reference indexes for disease condition monitoring and prognosis evaluation.

The past, present and future of Alzheimer's disease - part 1: the past / O passado, presente e futuro da doença de Alzheimer - parte 1: o passado

Abstract Background Alzheimer's disease (AD) was described in 1907, and since then it changed from a relatively rare condition to one of the most prevalent diseases. Objective To describe the evolution of the notions of dementias and AD, and to investigate the reasons for the increase in scientific interest in AD. Methods A historical analysis was carried out on knowledge about dementia, the site of mental activity, the relationships between brain diseases and mental activity, and on the advances in research about AD, since its discovery until the publication of the amyloid cascade hypothesis in 1992. A search was carried out in the National Library of Medicine (PubMed) for scientific articles that included the terms dementia or AD over 50 years, from 1972 to 2021. Results The scientific research on AD increased from 615 papers with the term AD in the first decade (1972-1981), to 100,028 papers in the last decade (2012-2021): an increase of 162.6 times whereas publications with the term dementia increased 28.6 times in the same period. In the 1960s and 1970s, a consensus was reached that AD is responsible for the majority of cases of dementia previously known as senile dementia. In the 1980s, beta-amyloid peptide was identified in the core of the senile plaque, hyperphosphorylated tau protein was found in neurofibrillary tangles, and a mutation was discovered in a hereditary form of AD. Conclusion The expansion of the concept of AD to include senile dementia, and the discoveries that occurred in the 1980s greatly expanded research in AD.

Resumo Antecedentes A doença de Alzheimer (DA) foi descrita em 1907 e, desde então, deixou de ser relativamente rara para se tornar uma das doenças mais prevalentes. Objetivo Descrever a evolução das noções sobre demências e DA e investigar as razões do aumento do interesse científico pela DA. Métodos Foi realizada uma análise histórica dos conhecimentos sobre demência, o local da atividade mental, as relações entre doenças cerebrais e a atividade mental, e sobre os avanços na pesquisa sobre a DA, desde a sua descoberta até a publicação da hipótese da cascata amiloide em 1992. Foi realizada uma busca na Biblioteca Nacional de Medicina dos Estados Unidos da América (PubMed) por artigos científicos que incluíssem os termos demência ou DA nos 50 anos, de 1972 a 2021. Resultados A pesquisa científica sobre DA aumentou de 615 artigos com o termo doença de Alzheimer na primeira década (1972-1981), para 100.028 artigos na última década (2012-2021): um aumento de 162,6 vezes enquanto as publicações com o termo demência aumentaram 28,6 vezes no mesmo período. Nas décadas de 1960 e 1970, chegou-se a um consenso de que a DA é responsável pela maioria dos casos de demência, anteriormente conhecida como demência senil. Na década de 1980, o peptídeo beta-amiloide foi identificado no núcleo da placa senil, a proteína tau hiperfosforilada foi encontrada em emaranhados neurofibrilares e uma mutação foi descoberta em uma forma hereditária de DA. Conclusão A expansão do conceito de DA para incluir a demência senil e as descobertas ocorridas na década de 1980 ampliaram enormemente a pesquisa em DA.

Research progress on repetitive transcranial magnetic stimulation in treatment of Alzheimer's disease / 中风与神经疾病杂志

@#Alzheimer's disease (AD) is a chronic neurodegenerative disease that occurs insidiously and progresses over time. Its main symptoms include memory and language impairments. The pathogenesis of AD remains unclear,and drug treatment for AD is still unsatisfactory,pointing to the need for a new approach to treating this disease. Existing research has shown that repetitive transcranial magnetic stimulation (rTMS) can improve the cognitive and neuropsychiatric symptoms of patients with AD,which provides a new idea for the treatment of AD. Exploring the mechanism of rTMS improving the clinical manifestations of patients with AD can promote our understand of the pathogenesis of AD. This article summarized the pathological changes and clinical features of AD as well as research progress on rTMS in the treatment of AD,aiming to provide new ideas for studying the pathogenesis and treatment of AD.

Analysis of potential biomarkers for behavioral and psychological symptoms in patients with Alzheimer′s disease continuum / 中华健康管理学杂志

Objectives:To analyze the potential biomarkers of behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer′s disease (AD) continuum.Methods:A prospective cohort study was consecutively conducted on 179 patients with AD continuum (135 presented with BPSD, 44 patients without BPSD as control) from Capital Medical University, Beijing Tiantan Hospital, the Chinese imaging biomarkers and lifestyle cohort between January 1, 2021 and December 31, 2022. Gender, age, body max index, education level, diagnosis, the apolipoprotein E epsilon4 allele (APOE ε4) carrier status, the scores of the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), cerebrospinal fluid (CSF) AD-related pathological biomarkers (Aβ 42, Aβ 40, Aβ 42/40, tTau, pTau181), and blood biomarkers (white blood cell count, red blood cell count, hemoglobin, platelet, total bilirubin, albumin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fasting glucose, erythrocyte sedimentation rate, homocysteine, vitamin B 12, folate) were compared between the two groups by using hypothesis testing and univariate logistic regression analysis. Multivariate logistic regression analysis was used to analyze the potential biomarkers associated with BPSD in patients with AD. Results:Among the 179 patients with AD continuum in the final analysis, 77 patients were men, 102 cases were women; 35 patients were identified with mild cognitive impairment (MCI) due to AD and 144 patients with AD dementia stage, the mean age was (66.54±9.75) years. Compared with those in control group, patients with BPSD had lower cerebrospinal fluid (CSF) Aβ 40 and blood hemoglobin levels [7.08 (4.42, 15.42) vs 9.62 (6.45, 12.12) pg/L, (132.70±13.37) vs (138.80±14.38) g/L] ( U=-1.856, t=2.579, P<0.05). The levels of CSF Aβ 40 ( OR=0.030, 95% CI: 0.001-0.760) and blood hemoglobin ( OR=0.051, 95% CI: 0.004-0.670) were independently negatively associated with BPSD in patients with AD continuum (both P<0.05). Conclusion:The decreased levels of CSF Aβ 40 and blood hemoglobin could be considered as potential biomarkers in detecting BPSD in patients with AD continuum.

Anti-amyloid-β disease-modifying therapies for Alzheimer′s disease: the dawn of a new era / 中华神经科杂志

Alzheimer′s disease (AD) is the most common neurodegenerative disease. Its etiology and pathogenesis remain unclear. Since its inception, the amyloid-β (Aβ) cascade hypothesis has dominated the field of AD research and has provided the intellectual framework for disease-modifying therapies. Nowadays, many Aβ-targeted therapies have been accelerated approval or received Food and Drug Administration′s breakthrough therapy designation which offers a new dawn for disease-modifying treating AD. This article reviews the research progress of clinical trials of Aβ-targeting modification therapies, and summarizes the lessons learned from the clinical failure with several classes of anti-Aβ drugs. Although many challenges remain, anti-Aβ therapies have become a promising treatment strategy for AD.

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease / 神经科学通报·英文版

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

Systematic review on nine hallmarks of neurodegenerative disease

Alzheimer's disease (AD) and Parkinson's disease (PD) are the primary diseases in neurodegenerative diseases. Nowadays, AD is common in one of the ten individuals whose age is more than 65, and its prevalence is kept on increasing with aging. Very few treatments and no effective treatments are available for curing neurodegenerative diseases. Pathogenesis of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, and their association with the nine hallmarks of aging were clearly described in this review. Instability in genomic, attrition in telomere, alterations in epigenetics, proteostasis loss, dysfunction in mitochondria, senescence in cells, sensing of deregulated nutrition, exhaustion of stem cells, and alterations in intercellular communication are the nine biological hallmarks of Aging. Improving the medical facilities for neurodegenerative diseases is very much essential. Doctors and researchers are doing surplus research to overcome the unavailability of proper treatments for such neurodegenerative diseases. Reason and the causes behind the diseases and their effects are explained in this review to enhance the further research to help the society.

Changes in serum miR-320a and AQP4 levels in patients with Alzheimer’s disease and their clinical significance / 中风与神经疾病杂志

@#Objective　To explore the changes and clinical significance of serum microRNA-320a (miR-320a) and aquaporin 4 (AQP4) levels in patients with Alzheimer’s disease (AD).Methods　Eighty patients with AD admitted to Puyang Oilfield General Hospital from January 2016 to April 2022 were selected as the AD group,and another 34 healthy people with physical examination in the same period were selected as the control group.qRT-PCR was used to detect serum miR-320a levels,and ELISA was used to detect serum amyloid-β (Aβ) 42,Aβ40,Aβ42/Aβ40,AQP4 levels,and the simple mental state examination (MMSE) was used to assess cognitive function.The relationship of serum miR-320a and AQP4 levels with Aβ42,Aβ40,Aβ42/Aβ40 levels and MMSE score in AD patients,and their diagnostic value for AD were analyzed.Results　Compared with the control group,serum Aβ42,Aβ42/Aβ40,miR-320a,AQP4 levels and MMSE scores were reduced and serum Aβ40 levels were increased in the AD group (P<0.05).Pearson/Spearman correlation analysis showed that serum miR-320a and AQP4 levels in AD patients were positively correlated with Aβ42,Aβ42/Aβ40 levels and MMSE scores,and negatively correlated with Aβ40 levels (P<0.05).The analysis of the working characteristic curve of subjects showed that the AUC of serum mir-320a and AQP4 levels in the diagnosis of AD alone and in combination were 0.802,0.819 and 0.913 respectively,the sensitivity was 83.75%,87.50% and 92.50% respectively,and the specificity was 70.59%,70.59% and 82.35% respectively.The combined diagnosis of the two can further improve the diagnostic value (P<0.05).Conclusion　Serum miR-320a and AQP4 levels are reduced in AD patients,both of which are associated with Aβ deposition and cognitive function in AD patients and can be used as auxiliary diagnostic indicators of AD.

Exosomes' roles in the pathogenesis of Alzheimer's disease and the diagnostic and therapeutic values / 中华老年医学杂志

Exosomes are nanoscal-scale vesicles containing a variety of proteins(HSP70, actin, Alix, etc.), lipids, mRNAs and miRNAs.They are commonly found in various tissues and cells of the organism.They are involved in processes such as intercellular communication, immune regulation and cell signaling pathway regulation, and then play an important role.Recent studies have shown that exosome-mediated intercellular signaling plays an important role in the progression of Alzheimer's disease(AD). This paper reviewed the general characteristics of exosomes, clarifies the possible role of exosomes in the pathogenesis of AD, and also discussed the application prospect and the related challenges of exosomes as a new potential option in the future treatment of AD.

Biofluid Biomarkers of Alzheimer's Disease: Progress, Problems, and Perspectives / 神经科学通报·英文版

Since the establishment of the biomarker-based A-T-N (Amyloid/Tau/Neurodegeneration) framework in Alzheimer's disease (AD), the diagnosis of AD has become more precise, and cerebrospinal fluid tests and positron emission tomography examinations based on this framework have become widely accepted. However, the A-T-N framework does not encompass the whole spectrum of AD pathologies, and problems with invasiveness and high cost limit the application of the above diagnostic methods aimed at the central nervous system. Therefore, we suggest the addition of an "X" to the A-T-N framework and a focus on peripheral biomarkers in the diagnosis of AD. In this review, we retrospectively describe the recent progress in biomarkers based on the A-T-N-X framework, analyze the problems, and present our perspectives on the diagnosis of AD.

Apolipoprotein E and Alzheimer's disease

Genetic variation in apolipoprotein E (APOE) influences Alzheimer's disease (AD) risk. APOE ε4 alleles are the strongest genetic risk factor for late onset sporadic AD. The AD risk is dose dependent, as those carrying one APOE ε4 allele have a 2-3-fold increased risk, while those carrying two ε4 alleles have a 10-15-fold increased risk. Individuals carrying APOE ε2 alleles have lower AD risk and those carrying APOE ε3 alleles have neutral risk. APOE is a lipoprotein which functions in lipid transport, metabolism, and inflammatory modulation. Isoform specific effects of APOE within the brain include alterations to Aβ, tau, neuroinflammation, and metabolism. Here we review the association of APOE with AD, the APOE isoform specific effects within brain and periphery, and potential therapeutics.

Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.

Clinical study on the treatment of QingxinWendan decoction in bipolar disorder manic episode patients / 中国医师杂志

Objective:To study the clinical effects of QingxinWendan decoction in the treatment of bipolar disorder (BD) manic episode.Methods:60 patients with BD manic episode treated in Hunan Brain Hospital from February 2020 to December 2020 were prospectively selected. They were included in the control group and the observation group according to the random alphabet method, with 30 cases in each group. The control group was treated with magnesium valproate sustained-release tablets, and the observation group was treated with Qingxin Wendan decoction combined with magnesium valproate sustained-release tablets. The curative effect was evaluated after 4 weeks of continuous treatment. The degree of mania before and after treatment was evaluated by Beck-Rafaelsen mania scale (BRMS); the cognitive function before and after treatment was evaluated by Wechsler Adult Intelligence Scale (WAIS-RC) and Wechsler Memory Scale (WMS); The levels of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), neuron specific enolase (NSE) and amyloid β protein (Aβ) levels were measured by enzyme linked immunosorbent assay (ELISA) before and after treatment. Spearman correlation analysis was used to analyze the correlation between serum NSE and Aβ levels and WAIS-RC and WMS scores in the two groups.Results:The curative effect of the observation group was better than that of the control group, with statistically significant difference ( P<0.05). After treatment, the BRMS scores of the control group and the observation group decreased (all P<0.05), and the BRMS scores of the observation group were lower than those of the control group ( P<0.05); After treatment, the WAIS-RC and WMS scores of the control group and the observation group increased (all P<0.05), and the WAIS-RC and WMS scores of the observation group were higher than those of the control group (all P<0.05). After treatment, the serum levels of IL-1β, TNF-α, NSE and Aβ in two groups were decreased (all P<0.05), and the levels of IL-1β, TNF-α, NSE and Aβ in the observation group were lower than those in the control group (all P<0.05). NSE and Aβ levels were negatively correlated with WAIS-RC and WMS scores (all P<0.05). Conclusions:Magnesium valproate sustained-release tablets combined with Qingxin Wendan decoction in the treatment of patients with BD manic episode were superior to magnesium valproate sustained-release tablets alone in reducing manic score, IL-1β, TNF-α, NSE and Aβ levels, and improving the cognitive function of patients. The use of QingxinWendan decoction on top of valproate extended-release tablet treatment for BD manic episode was superior to treatment with valproate extended-release tablets alone in reducing mania scores, IL-1β, TNF-α, NSE and Aβ levels, as well as improving patients' cognitive function.

Improvement of astaxanthin on learning and memory ability of vascular dementia mice / 解剖学报

Objective To study the effect and mechanism of astaxanthin on learning and memory ability of vascular dementia (VaD) mice. Methods The mice were used to establish VaD model by occlusion of bilateral common carotid artery. The mice were randomly divided into sham group, model group, astaxanthin low-dose group and astaxanthin high-dose group and then given corresponding forms of drug treatments. Morris water maze was used to investigate the learning, memory and space exploration abilities of mice in each group. At the same time, the pathological morphology of brain neurons, the expression of amyloid beta-peptides 42(Aβ

Hypothesis on ontogenesis and pathophysiology of Alzheimer's disease

Abstract Alzheimer's disease is a neurodegenerative condition that causes changes in memory and cognition, in addition to behavioral disorders, and most commonly affects the elderly. Several studies in the literature have presented therapeutic measures in an attempt to interfere with the pathogenic mechanisms of the disease and to mitigate its clinical manifestations. Some factors, such as excitotoxicity, cholinergic dysfunctions, oxidative stress, tau protein hyperphosphorylation, changes in amyloid-beta peptide metabolism, herpes viruses, apolipoprotein E, glycogen synthase kinase 3, insulin resistance, and the endocannabinoid system seem to be related to pathophysiology of Alzheimer's disease. Given this, a literature review was carried out to address the molecular mechanisms associated with the pathophysiological hypotheses previously mentioned, aiming to better understanding their underlying causes and contributing to possible pharmacological strategies about treatment of the disease.

Investigation of anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L): in vitro and in vivo studies / Investigación de la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L): estudios in vitro e in vivo

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.

La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.

Doença de Alzheimer de início precoce (DAIP): características neuropatológicas e variantes genéticas associadas / Early-onset Alzheimer's Disease (EOAD): neuropathological characteristics and associated genetic variants

RESUMO A doença neurodegenerativa mais comum no mundo é a doença de Alzheimer (DA), e 10% dos casos apresentam sintomas antes dos 65 anos, quase todos com associação genética, com hereditariedade autossômica dominante e penetrância entre 92 a 100% dos portadores. Na presente revisão, realizamos uma busca sobre as variantes genéticas associadas à doença de Alzheimer de início precoce (DAIP), enfatizando as características associadas mais importantes e as principais mutações já descritas. Os genes mais comumente relacionados com o surgimento da DAIP são APP, PSEN1, PSEN2 e MAPT, e mutações nestes afetam o metabolismo e a estrutura destas proteínas, resultando em acúmulos de peptídeo Aβ que causam inflamação e toxicidade no cérebro, levando à ativação da micróglia e promovendo a liberação de fatores neurotóxicos e pró-inflamatórios que aceleram a neurodegeneração. O gene PSEN1 é responsável por 70% das mutações conhecidas da DAIP, sendo a L166P associada à idade de ocorrência da doença abaixo dos 30 anos. Mutações em APP levam à agregação da proteína em placas neurodegenerativas. Todas as mutações descritas para MAPT estão associadas a um aumento dos emaranhados neurofibrilares. O polimorfismo E4 da Apolipoproteína E (APOE) influencia o aumento no risco de DAIP elevando as chances em três vezes para portadores heterozigotos e entre oito a dez vezes para os homozigotos. Apenas 5% das mutações associadas à DAIP são conhecidas, e novos estudos apresentam outros genes candidatos, bem como a importância de alterações epigenéticas na gênese desta doença.

SUMMARY The most common neurodegenerative disease in the world is Alzheimer's Disease (AD). Ten percent of Alzheimer patients experience symptoms before the age of 65, and almost all of them present genetic features of autosomal dominant inheritance nature, and penetrance of 92 to 100%. In the present review, we searched for genetic variants associated with early onset Alzheimer's disease (EOAD), emphasizing the most important characteristics and the main mutations. The genes most commonly related to the onset of EOAD are APP, PSEN1, PSEN2 and MAPT, whose mutations affect the metabolism and structure of these proteins. This process results in accumulations of Aβ peptide that leads to activation of the microglia and release of neurotoxic and pro-inflammatory factors that accelerate neurodegeneration. The PSEN1 gene is responsible for 70% of the known mutations in EOAD, while L166P is associated with below 30 years as the starting age of occurrence. APP mutations lead to protein aggregation in neurodegenerative plaques. All of the mutations described for MAPT are associated with an increase in neurofibrillary tangles. The E4 polymorphism of Apolipoprotein E (APOE) influences an increased risk of EOAD increasing up to three times the chances for heterozygous, and between eight and ten times for homozygotes carriers. Only 5% of the mutations associated with EOAD are known; new studies will show other candidate genes, as well as the importance of epigenetic factors changes in the etio-pathogenesis of this disease.

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (