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.

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.

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.

Role of hippocampal β-amyloid 42 deposition-induced accumulation of neutrophils in blood-brain barrier damage caused by sevoflurane anesthesia in aged rats / 中华麻醉学杂志

Objective:To evaluate the role of hippocampal β-amyloid 42 (Aβ 42) deposition-induced accumulation of neutrophils in blood-brain barrier damage caused by sevoflurane anesthesia in aged rats. Methods:Seventy-two healthy male Wistar rats in which IT catheters were successfully planted, aged 18-20 months, weighing 600-650 g, were divided into 4 groups ( n=18 each) using a random number table method: control group (group C), γ-secretase inhibitor DAPT group (group D), sevoflurane anesthesia group (group S) and DAPT plus sevoflurane anesthesia group (group DS). Dimethyl sulfoxide 10 μl was intrathecally injected in group C and group S, and 30 min later group C inhaled 60% oxygen for 2 h, and group S inhaled 3.6% sevoflurane and 60% oxygen for 2 h and tibial fracture surgery was performed at the same time.DAPT 10 μl was intrathecally injected in group D and group DS, and 30 min later group D inhaled 60% oxygen for 2 h, and group DS inhaled 3.6% sevoflurane and 60% oxygen for 2 h and tibial fracture surgery was performed at the same time.The fear conditioning test was performed at 12 h after the end of treatment in each group, and the ratio of time spent freezing was calculated.The rats were sacrificed after the end of behavioral test, and hippocampal tissues were removed for determination of the expression of Aβ 42, occludin and matrix metalloproteinase-9 (MMP-9) (by Western blot), neutrophil count (by immuno-histochemistry), and content of Evans blue (EB) (by EB staining). Results:Compared with group C, the ratio of time spent freezing was significantly decreased, the expression of Aβ 42 and MMP-9 was up-regulated, the expression of occludin was down-regulated, the neutrophil count and content of EB were increased in group S and group DS ( P<0.05), and no significant change was found in the parameters mentioned above in group D ( P>0.05). Compared with group S, the ratio of time spent freezing was significantly increased, the expression of Aβ 42 and MMP-9 was down-regulated, the expression of occludin was up-regulated, the neutrophil count and content of EB were decreased in group DS ( P<0.05). Conclusion:The mechanism by which sevoflurane anesthesia leads to postoperative cognitive dysfunction is related to hippocampal Aβ 42 deposition-induced accumulation of neutrophils and causing damage to blood-brain barrier in aged rats.

Advances in immunoinflammatory regulation of β amyloid in age-related macular degeneration / 中华眼底病杂志

Age-related macular degeneration (AMD) is an age-related degenerative disease with complex pathogenesis, whose initial lesion is accompanied with immune inflammatory response. Amyloid beta (Aβ), a small-molecule protein generated by the hydrolysis of amyloid precursor protein, as the main component, is involved in the formation of drusen, which serves as the early characteristic of AMD. In the local inflammatory response of AMD, Aβ is an important pathological deposit, promoting the proliferation and differentiation of macrophages as well as changing their morphology to accelerate the progression of AMD. In addition, Aβ can also regulate immune molecules and the complement system by activating inflammatory pathways, thus mediating chronic retinal inflammation and promoting the course of AMD. However, since AMD is not caused by inflammation alone, only the immunosuppression may not be effective in inhibiting the course of AMD, and thus the future development is to rebalance the disordered immune system in AMD patients eyes.

Primary Age-Related Tauopathy: An Elderly Brain Pathology Frequently Encountered during Autopsy

Due to the progressive aging of Korean society and the introduction of brain banks to the Korean medical system, the possibility that pathologists will have access to healthy elderly brains has increased. The histopathological analysis of an elderly brain from a subject with relatively well-preserved cognition is quite different from that of a brain from a demented subject. Additionally, the histology of elderly brains differs from that of young brains. This brief review discusses primary age-related tauopathy; this term was coined to describe elderly brains with Alzheimer’s diseasetype neurofibrillary tangles mainly confined to medial temporal structures, and no β-amyloid pathology.

Effect of Danggui Shaoyaosan on Copper Ion-mediated Aβ Aggregation in AD Cell Model / 中国实验方剂学杂志

Objective:To investigate the effect of copper ion(Cu2+) on the aggregation and neurotoxicity of Aβ, and affirm the role of Danggui Shaoyaosan in vitro,the Neuroblastoma (SH-SY5Y) cells treated with β-amyloid 1-42 (Aβ1-42) and Cu2+ were used as a vitro models of Alzheimer's disease(AD). Method:Aβ 1-42 (20 μmol·L-1) was reacted with different concentrations of copper sulfate (CuSO4,20,40 μmol·L-1), and then the thioflavine T (ThT) staining method was used to detect the Aβ aggregation state. The Aβ aggregation status was also detected by ThT staining in the Aβ1-42-Cu2+ group(20+20 μmol·L-1), and Danggui Shaoyaosan groups(1.6,3.2,6.4 mg·L-1).The SH-SY5Y cells were cultured and incubated with different concentrations of Aβ1-42(1.25,2.5,5,10,20,40 μmol·L-1) and Danggui Shaoyaosan(1.6, 3.2, 6.4,12.8 mg·L-1) for 24 h. Subsequently, SH-SY5Y cells were incubated with Aβ1-42 (20 μmol·L-1) and CuSO4(20 μmol·L-1) in the Aβ1-42-Cu2+ group, and incubated with Aβ1-42 (20 μmol·L-1), Danggui Shaoyaosan (1.6 mg·L-1) and CuSO4 (20 μmol·L-1) in Danggui Shaoyaosan group. Control group was added with the medium. After 24 h of co-action, the cell viability was detected by the methylthiazolyl tetrazolium (MTT) assay. The morphology of the cells was photographed by microscopy. The intracellular extracellular Aβ1-42 aggregation was detected by Western blot. Result:Cu2+ and Aβ1-42 bound to more and larger Aβ aggregates compared with the Aβ1-42 group. Compared with the normal group, cell viability was significantly reduced (PPβ1-42 aggregation was increased(PPβ-Cu2+ (PPβ1-42 protein (PPConclusion:Cu2+ can increase the aggregation and toxicity of Aβ; Danggui Shaoyaosan can significantly reduce the damage of SH-SY5Y cells induced by Cu2+-mediated Aβ aggregation, promote Aβ endocytosis, reduce extracellular Aβ aggregation and increase cell viability.

Effects of Mediterranean diet on Alzheimer's disease / 中华老年医学杂志

Alzheimer's disease (AD)is most common in all dementia types in the elderly.Various researches have been done for studying its pathogenesis,but no single mechanism can explain all its pathological changes.AD is currently incurable and no effective treatment measures are available.So it is of prime importance to prevent the occurrence of AD.In the process of exploring the pathogenesis and treatment of AD,more and more attention is being paid to the role of diet and nutrition in the occurrence and development of AD.Mediterranean diet(MeDi)has been proved to have an unvarying role in the occurrence and development of Alzheimer's disease.This paper reviewed the relevant literatures and summarized the role of MeDi in AD,in order to provide the theoretical supports for dietary intervention and nutritional therapy in AD treatment.

Focused ultrasound and Alzheimer's disease: a systematic review / Ultrassonografia focalizada e doença de Alzheimer: uma revisão sistemática

ABSTRACT Alzheimer's disease (AD) affects millions of people, however, there is still no effective treatment. The use of focused ultrasound with microbubbles (FUS-MB) for the opening of the blood-brain barrier has been recently studied and may become a promising therapeutic target. Objective: To discuss the use of FUS-MB for the treatment of AD and to present some of the techniques used. Methods: A systematic review was performed of MEDLINE/PubMed and Biblioteca Virtual em Saúde (BVS) services, using the keywords: focused ultrasound, Alzheimer, amyloid-b. Original articles were included in the study; studies that did not focus on Alzheimer's treatment were excluded. Results: Fifteen original studies were selected. Preclinical trials were able to reduce amyloid-b plaques and tau phosphorylation, improving cognitive performance in AD animals. Conclusion: The results are very promising, but the therapy still requires maturation. Further studies are needed to systematize all the techniques used and their effects in order to enable use in humans.

RESUMO A doença de Alzheimer (DA) afeta milhões de pessoas, porém, ainda não há um tratamento efetivo. O uso de ultrassonografia focalizada com microbolhas (FUS-MB) para a abertura da barreira hematoencefálica (BHE) tem sido objeto de estudos recentes, podendo tornar-se um alvo terapêutico bastante promissor. Objetivo: Discutir o uso da FUS-MB para o tratamento da DA e apresentar algumas das técnicas utilizadas. Métodos: Revisão sistemática através dos serviços MEDLINE/PubMed e Biblioteca Virtual em Saúde (BVS), através das seguintes palavras-chaves: focused ultrasound, Alzheimer, amyloid-b. Foram incluídos no estudo artigos originais. Foram excluídos estudos que não tinham o tratamento do Alzheimer como foco. Resultados: Foram selecionados 15 estudos originais. Os resultados pré-clínicos são positivos para redução de placas amiloides, fosforilação da proteína tau e sobre desempenho cognitivo de animais com DA. Conclusão: Os resultados são promissores, mas terapia ainda necessita de aperfeiçoamento, necessitando de mais estudos que sistematize todas as técnicas e seus efeitos, para ser possível o seu uso em humanos.

Terapia antiamiloide: uma nova estratégia para tratamento da doença de Alzheimer / Antiamyloid therapy: a new strategy for treating Alzheimer's disease

A doença de Alzheimer é a patologia neurodegenerativa mais frequente associada à idade, cujas manifestações cognitivas e neuropsiquiátricas resultam em deficiência progressiva e incapacitação. Existem vários tipos de terapias farmacológicas que visam melhorar a qualidade de vida do paciente afetado por esta patologia. Muitos medicamentos são usados há muito tempo para o tratamento da doença, sendo os inibidores da colinesterase as drogas de primeira escolha para o tratamento, mas nenhum deles regride a progressão da doença de Alzheimer. Novos estudos têm sido realizados, com o objetivo de procurar um novo medicamento que seja capaz de ajudar em sua regressão. Ainda, novos tratamentos, como a terapêutica antiamiloide, são opções que estão sendo observados para uma melhor terapêutica. Estes tratamentos são descritos nesta revisão, que teve como objeitvo analisar os benefícios do tratamento da doença de Alzheimer, por meio da terapêutica antiamiloide, em que se enquadra a imunoterapia.(AU)

Alzheimer's disease is the most common neurodegenerative disorder associated with age, whose cognitive and neuropsychiatric manifestations result in progressive disability and incapacitation. There are several types of pharmacological therapies aimed at improving the patient's quality of life affected by this disease. Many medications have long been used for the treatment of the disease, with cholinesterase inhibitors being the drugs of first choice for the treatment but none of them regress the progression of Alzheimer's disease. Further studies have been made to search a new drug able to assist in the regression of the disease. In addition, new therapies such as the anti-amyloid one are options that are being observed to improve treatment. These therapies are described in this review, which aims at analyzing the benefits of anti-amyloid therapy for Alzheimer's disease, in which immunotherapy is included.(AU)

Effects of different anesthesia modes on POCD occurrence, serum S-100β and Aβ1-42 proteins in TURP patients after elderly patients / 中国医师杂志

Objective To investigate the effects of general anesthesia and hard epidural anesthesia on the incidence of postoperative cognitive dysfunction (POCD),serum S-100β and Aβ1-42 protein in elderly patients with transurethral resection of the prostate (TURP).Methods 120 cases of elderly male patients who wanted to implement TURP were enrolled in this study.From March 2014 to August 2016,60 patients underwent general anesthesia (general anesthesia group) and 60 patients underwent epidural anesthesia (hard epidural Group).The effects of two anesthesia methods on the cognitive function,serum S-100 β and Aβ1-42 protein were compared.Results There was no significant difference in mini-mental state examination (MMSE) score in preoperative,postoperative 12 h,postoperative 24 h,postoperative 72 h,and postoperative 1 week between hard epidural group and general anesthesia group (P ＞ 0.05).The MMSE scores at 12 h,24 h and 72 h after operation in both groups were significantly lower than those before operation in both groups (P ＜0.05).There was no significant difference in clock drawing task (CDT) score in preoperative,24 h after operation,72 h after operation and one week after operation (P ＞ 0.05).The CDT scores of both groups at 12 h,24 h,72 h after operation were significantly lower than those before operation (P ＜0.05).There was no significant difference in serum S-100β levels between the two groups at preoperative and 12 h,72 h after operation (P ＞0.05).Serum S-100β levels at 12 h and 72 h after surgery in both groups were significantly higher than those before surgery (P ＜ 0.05).There was no significant difference in preoperative and postoperative 12 h,postoperative between hard epidural group and general anesthesia group (P ＞ 0.05).Serum Aβ1-42 levels at preoperative,12 h and 72 h after operation in both groups were significantly lower than those before operation (P ＜ 0.05).There was not statistically significant in the incidence of POCD between hard epidural group [28.33 ％ (17/60)] and general anesthesia group [35％ (21/ 60)] (P ＞ 0.05).Conclusions There was no significant difference in the incidence of POCD between general anesthesia and hard epidural anesthesia group in elderly patients with TURP.The incidence of POCD in elderly patients was related to the decrease of serum S-100β and the decrease of Aβ1-42.

Blood biomarkers of post-stroke cognitive impairment / 国际脑血管病杂志

The diagnosis of post-stroke cognitive impairment (PSCI) mainly depends on clinical manifestation and scale assessment now, but lacks specificity. Studies in recent years have shown that there are biomarkers closely related to PSCI. This article reviews the blood biomarkers of PSCI.

Effects of NADPH Oxidase Inhibitors and Mitochondria-Targeted Antioxidants on Amyloid β₁₋₄₂-Induced Neuronal Deaths in Mouse Mixed Cortical Cultures / 전남의대학술지

The Amyloid β peptide (Aβ) is a main component of senile plaques in Alzheimer's disease. Currently, NADPH oxidase (NOX) and mitochondria are considered as primary sources of ROS induced by Aβ. However, the contribution of NOX and mitochondria to Aβ-induced ROS generation has not been well defined. To delineate the relative involvement of NOX and mitochondria in Aβ-induced ROS generation and neuronal death in mouse cortical cultures, we examined the effect of NOX inhibitors, apocynin and AEBSF, and the mitochondria-targeted antioxidants (MTAs), mitotempol and mitoquinone, on Aβ-induced ROS generation and neuronal deaths. Cell death was assessed by measuring lactate dehydrogenase efflux in bathing media at 24 and 48 hrs after exposure to Aβ₁₋₄₂. Aβ₁₋₄₂ induced dose- and time-dependent neuronal deaths in cortical cultures. Treatment with 20 µM Aβ₁₋₄₂ markedly and continuously increased not only the DHE fluorescence (intracellular ROS signal), but also the DHR123 fluorescence (mitochondrial ROS signal) up to 8 hrs. Treatment with apocynin or AEBSF selectively suppressed the increase in DHE fluorescence, while treatment with mitotempol selectively suppressed the increase in DHR123 fluorescence. Each treatment with apocynin, AEBSF, mitotempol or mitoquinone significantly attenuated the Aβ₁₋₄₂-induced neuronal deaths. However, any combined treatment with apocynin/AEBSF and mitotempol/mitoquinone failed to show additive effects. These findings indicate that 20 µM Aβ₁₋₄₂ induces oxidative neuronal death via inducing mitochondrial ROS as well as NOX activation in mixed cortical cultures, but combined suppression of intracellular and mitochondrial ROS generation fail to show any additive neuroprotective effects against Aβ neurotoxicity.

Role of Sleep Disturbance in the Trajectory of Alzheimer's Disease

Sleep disturbances such as insomnia, hypersomnia, and circadian rhythm disturbance are common in normal elderly and Alzheimer's disease (AD) patients. To date, special attention has been paid to sleep disturbance in the clinical course of AD insofar as the interaction of sleep disturbance with the pathogenesis of AD may impact the clinical course and cognitive function of AD patients. This review covers the bidirectional relationship between sleep disturbance and AD pathogenesis; the associations between sleep disturbance and AD-specific neurotransmitters, brain structure, and aspects of sleep disturbance in each phase of AD; and the effects of sleep disturbance on the cognitive functions of patients in each phase of AD. We consider several factors required to exactly interpret the results and suggest a direction for future studies on the role of sleep disturbance in AD.

NADPH Oxidase Mediates β-Amyloid Peptide-Induced Neuronal Death in Mouse Cortical Cultures / 전남의대학술지

β-Amyloid peptide (Aβ) is the main component of senile plaques in patients with Alzheimer's disease, and is known to be a main pathogenic factor of the disease. Recent evidence indicates that activation of NADPH oxidase (NOX) in microglia or astrocytes may be a source of Aβ-induced reactive oxygen species (ROS). We investigated the role of neuronal NOX in Aβ-induced neuronal death in mouse mixed cortical cultures. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media 24 or 48 hr after exposure to Aβ₂₅₋₃₅, a fragment of Aβ with an equivalent neurotoxic effect. Aβ₂₅₋₃₅ induced neuronal death in concentration- and time- dependent manners with apoptotic features. Neuronal death was significantly attenuated, not only by anti-apoptotic drugs, such as z-VAD-fmk and cycloheximide, but also by antioxidants, such as trolox, ascorbic acid, and epigallocatethin gallate. We also demonstrated that treatment with 20 µM Aβ₂₅₋₃₅ increased fluorescent signals in mixed cortical cultures, but produced only weak signals in pure astrocyte cultures in the presence of 2',7'-dichlorofluorescin diacetate (DCF-DA), an indicator for intracellular ROS. Increased DCF-DA fluorescence was markedly inhibited, not only by trolox, but also by selective NOX inhibitors, such as apocynin and AEBSF. Western blot analyses revealed that Aβ₂₅₋₃₅ increased the expression of gp91phox, a main subunit of NOX in cells. The above antioxidants, apocynin, and AEBSF significantly attenuated neuronal death induced by Aβ₂₅₋₃₅. Furthermore, the gp91phox-specific siRNA-based knockdown of NOX significantly inhibited neuronal death. These results suggest that activation of neuronal NOX is involved in Aβ25-35-induced neuronal death.

Antagonism of lovastatin on oxidative stress and apoptosis in primary rat hippocampal neurons induced by β-amyloid peptide / 中华病理学杂志

Objective@#To investigate the effect of lovastatin on oxidative stress and apoptosis in neurons induced by β-amyloid peptide (Aβ).@*Methods@#Primary culture of rat hippocampal neuron was treated with Aβ oligomers alone or combined with lovastatin. The levels of OH-, H2O2, O2·-, malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were measured by biochemical methods and protein expression of caspase-3 and bcl-2 was detected by Western blot.@*Results@#As compared with the control group, treatment of 0.5 μmol/L Aβ oligomers for 48 h led to significant increase of OH-, H2O2, O2·- and malondialdehyde content, inhibition of SOD and GSH-PX activities, enhanced caspase-3 expression and decreased bcl-2 expression. Interestingly, these neurotoxic modifications on the levels of OH-, H2O2, O2·- and malondialdehyde content, SOD and GSH-PX activities, and the protein expression of cleaved caspase-3 and bcl-2 were significantly attenuated when the cells were pretreated with 0.1 μmol/L lovastatin for 24 h before exposure of Aβ oligomers.@*Conclusion@#Lovastatin may play an important role in antagonizing the neurotoxicity of Aβ through a mechanism likely related to the inhibition of oxidative stress.

NADPH Oxidase Mediates β-Amyloid Peptide-Induced Neuronal Death in Mouse Cortical Cultures / 전남의대학술지

β-Amyloid peptide (Aβ) is the main component of senile plaques in patients with Alzheimer's disease, and is known to be a main pathogenic factor of the disease. Recent evidence indicates that activation of NADPH oxidase (NOX) in microglia or astrocytes may be a source of Aβ-induced reactive oxygen species (ROS). We investigated the role of neuronal NOX in Aβ-induced neuronal death in mouse mixed cortical cultures. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media 24 or 48 hr after exposure to Aβ₂₅₋₃₅, a fragment of Aβ with an equivalent neurotoxic effect. Aβ₂₅₋₃₅ induced neuronal death in concentration- and time- dependent manners with apoptotic features. Neuronal death was significantly attenuated, not only by anti-apoptotic drugs, such as z-VAD-fmk and cycloheximide, but also by antioxidants, such as trolox, ascorbic acid, and epigallocatethin gallate. We also demonstrated that treatment with 20 µM Aβ₂₅₋₃₅ increased fluorescent signals in mixed cortical cultures, but produced only weak signals in pure astrocyte cultures in the presence of 2',7'-dichlorofluorescin diacetate (DCF-DA), an indicator for intracellular ROS. Increased DCF-DA fluorescence was markedly inhibited, not only by trolox, but also by selective NOX inhibitors, such as apocynin and AEBSF. Western blot analyses revealed that Aβ₂₅₋₃₅ increased the expression of gp91phox, a main subunit of NOX in cells. The above antioxidants, apocynin, and AEBSF significantly attenuated neuronal death induced by Aβ₂₅₋₃₅. Furthermore, the gp91phox-specific siRNA-based knockdown of NOX significantly inhibited neuronal death. These results suggest that activation of neuronal NOX is involved in Aβ25-35-induced neuronal death.

Amyloid-beta immunotherapy: the hope for Alzheimer disease? / Inmunoterapia beta-amiloide: ¿la esperanza para la enfermedad de Alzheimer?

Abstract Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

Resumen La enfermedad de Alzheimer (EA) es la forma más frecuente de demencia de inicio en el adulto, caracterizada por un deterioro progresivo en la cognición y la memoria. No hay cura para la enfermedad y los tratamientos actuales son sólo sintomáticos. El descubrimiento de fármacos es un proceso costoso y que consume mucho tiempo; en la última década no se han encontrado nuevos fármacos para la EA a pesar de los esfuerzos de la comunidad científica y las compañías farmacéuticas. La inmunoterapia contra Aβ es uno de los enfoques más prometedores para modificar el curso de la EA. Esta estrategia terapéutica utiliza péptidos sintéticos o anticuerpos monoclonales (mAb) para disminuir la carga de Aβ en el cerebro y retardar la progresión de la enfermedad. Por lo tanto, este artículo discutirá los principales aspectos de la neuropatogénesis de la EA, el tratamiento farmacológico clásico, así como la inmunización activa y pasiva describiendo los prototipos de fármacos evaluados en diferentes ensayos clínicos.

Perspectives for treating Alzheimer's disease: a review on promising pharmacological substances / Perspectivas no tratamento da doença de Alzheimer: uma revisão sobre substâncias farmacológicas promissoras

ABSTRACT CONTEXT AND OBJECTIVE: Dementia is a syndrome characterized by functional and cognitive decline. Alzheimer's disease (AD) is one of the most common causes of dementia and has high prevalence among the elderly. It is known that there is no drug capable of interfering with the course of the disease. Research on treatments for AD has been marked by the appearance of new drugs and their abandonment. This study aimed to describe drugs that have been studied with regard to treating AD and which are capable of influencing the course of the disease. DESIGN AND SETTING: Narrative review on original articles published worldwide. METHODS: A systematized search was conducted in the PubMed/MEDLINE, Cochrane Library/Cochrane and SciELO/Bireme databases. The descriptors "Molecular Mechanisms of Pharmacological Action" and "Drug Therapy" were each combined with the descriptor "Alzheimer disease". All of these can be found in MeSH and DeCS. These descriptors were used alone or in combination, and a filter specifying publication between January 2009 and October 2015 in English, Spanish or Portuguese was set. RESULTS: 6,888 articles were found, of which 37 were included in this review; 70.3% of the articles selected were of good quality with low or unclear risk of bias. 86 drugs were considered promising for AD treatment and these were classified into 20 pharmacological categories. CONCLUSION: There are no drugs capable of influencing the course of AD such that treatments are safe and effective. However, immunomodulators stood out as promising, given their effectiveness and quality in the articles analyzed.

RESUMO CONTEXTO E OBJETIVO: A demência é uma síndrome caracterizada por declínio funcional e cognitivo, sendo a doença de Alzheimer (DA) uma das causas mais comuns e de alta prevalência em idosos. Sabe-se que não há medicamento capaz de interferir no curso da doença e as pesquisas para o tratamento da DA têm sido marcadas pelo surgimento e abandono de novas drogas. O objetivo deste estudo foi descrever as drogas capazes de influenciar o curso da DA que têm sido estudadas para o tratamento da doença. TIPO DE ESTUDO E LOCAL: Revisão narrativa de artigos originais publicados mundialmente. MÉTODOS: Foi realizada uma busca sistematizada nas bases de dados PubMed/MEDLINE, Cochrane Library/Cochrane e SciELO/Bireme. Cada um dos seguintes descritores "Mecanismos Moleculares de Ação Farmacológica" e "Quimioterapia" foram combinados com o descritor "Doença de Alzheimer", todos encontrados no MeSH e DeCS. Os descritores foram usados sozinhos ou em combinação, fixando como filtros as publicações de 2009 a 2015, em língua inglesa, espanhola e portuguesa. RESULTADOS: Foram encontrados 6.888 artigos, dos quais 37 foram incluídos nesta revisão; 70,3% dos artigos selecionados tiveram boa qualidade com baixo ou indefinido risco de viés. Foram elencadas 86 drogas promissoras ao tratamento da AD. Elas foram classificadas em 20 categorias farmacológicas. CONCLUSÃO: Não há fármacos capazes de interferir no curso da DA com efetividade e segurança no tratamento. Contudo, os imunomoduladores foram considerados promissores devido ao fato de apresentarem efetividade e qualidade nos artigos analisados.