Rehabilitación Neurocognitiva en Enfermedades Neurodegenerativas. Un Enfoque para Ralentizar el Deterioro Neurológico en Demencias / Neurocognitive Rehabilitation in Neurodegenerative Diseases. An Approach to Slowing Neurological Impairment in Dementias

Resumen El incremento de la incidencia y prevalencia de las patologías Parkinson y Alzheimer generan una alarma en los sistemas de salud debido a sus consecuencias en los individuos, familia y sociedad. El desarrollo de tratamientos no farmacológicos dirigidos a la rehabilitación cognitiva abre nuevas posibilidades para el incremento de la calidad de vida de estos pacientes.

Abstract The increase in the incidence and prevalence of Parkinson's and Alzheimer's diseases is causing alarm in health systems due to their consequences on individuals, families, and society. The development of non-pharmacological treatments aimed at cognitive rehabilitation opens new possibilities for increasing the quality of life of these patients.

Aloe vera: capacidad antioxidante y uso potencial como agente terapéutico en el tratamiento del Alzheimer mediante evaluación in silico / Aloe vera: antioxidant capacity and potential use as therapeutic agent in the treatment of Alzheimer's through in silico evaluation

Resumen: El gel de Aloe vera es considerado una fuente natural de múltiples beneficios, originados por la acción combinada de vitaminas, aminoácidos, compuestos fenólicos, enzimas, minerales, ácidos orgánicos, lípidos y carbohidratos, que se relacionan con la mejora de enfermedades neuro-degenerativas como Alzheimer. Los ensayos in vitro e in silico permiten confirmar e identificar posibles beneficios de esta planta y sus compuestos en enfermedades. El objetivo del presente trabajo fue evaluar la actividad antioxidante del gel de A. vera y mediante análisis in silico, establecer el potencial terapéutico de sus compuestos bioactivos en la enfermedad de Alzheimer. Se obtuvieron hojas de A. vera, de las que se extrajo el gel, retirando el exocarpio, se liofilizó y almacenó hasta su uso. Se caracterizó la capacidad antioxidante, se cuantificaron los compuestos fenólicos y flavonoides y se analizó la relación que existe entre los parámetros mediante correlación de Pearson. Mediante análisis in silico se evaluó el potencial de interacción de 8 compuestos del gel con la proteína gamma secretasa. El gel de A. vera obtuvo alta capacidad antioxidante por ABTS, DPPH, radical OH y poder reductor, usando bajas concentraciones para inhibir el 50 % de los radicales, y correlaciones positivas con fenoles totales y flavonoides. En el estudio in silico el compuesto que presentó mejor unión con gamma secretasa fue aloe-emodina, con menor energía libre de unión y menor concentración de constante de inhibición, sugiriendo su potencial uso como coadyuvante en el tratamiento de la enfermedad de Alzheimer.

Abstract: Aloe vera gel is considered a natural source of multiple benefits, originated by the combined action of vitamins, amino acids, phenolic compounds, enzymes, minerals, organic acids, lipids and carbohydrates, which are related to the improvement of neuro-degenerative diseases such as Alzheimer's. In vitro and in silico tests allow us to confirm and identify possible benefits of this plant and its compounds in diseases. The objective of the present study was to evaluate the antioxidant activity of A. vera gel and, through in silico analysis, to establish the therapeutic potential of its bioactive compounds in Alzheimer's disease. A. vera leaves were obtained, from which the gel was extracted, removing the exocarp, lyophilized and stored until use. The antioxidant capacity was characterized, the phenolic compounds and flavonoids were quantified, and the relationship between the parameters was analyzed using Pearson correlation. The interaction potential of 8 compounds in the gel with the gamma secretase protein was evaluated through in silico analysis. The A. vera gel obtained high antioxidant capacity due to ABTS, DPPH, OH radical and reducing power, using low concentrations to inhibit 50 % of the radicals, and positive correlations with total phenols and flavonoids. In the in silico study, the compound that showed the best binding with gamma secretase was aloe-emodin, with lower binding free energy and lower inhibition constant concentration, suggesting its potential use as an adjuvant in the treatment of Alzheimer's disease.

Aducanumab: una mirada dos años después de su aprobación / Aducanumab: A look two years after its approval

Abstract Alzheimer's disease is the leading cause of dementia worldwide and a critical public health problem. While deaths from cardiovascular diseases have decreased, those attributed to Alzheimer's disease have increased in recent years with no curative treatment to date. In this context, effective treatment development has become a global priority. Aducanumab is a human anti-amyloid β monoclonal antibody approved by the FDA in June 2021 for the treatment of Alzheimer's disease but failed to show the expected clinical efficacy in phase III trials. This review analyzes the history of its controversial acceptance, implications, and prospects for future treatment.

Resumen La enfermedad de Alzheimer es la principal causa de demencia en todo el mundo y representa un importante problema de salud pública. Si bien las muertes por enfermedades cardiovasculares han disminuido, las atribuidas a la enfermedad de Alzheimer han aumentado en los últimos años y hasta la fecha no existe tratamiento curativo. Por este motivo, el desarrollo de un tratamiento eficaz se ha convertido en una prioridad mundial. Aducanumab es un anticuerpo monoclonal anti-amiloide β humano aprobado para el tratamiento de la enfermedad de Alzheimer en junio de 2021 por la FDA, sin la eficacia clínica esperada en los ensayos de fase III. Esta revisión analiza la historia de su controvertida aceptación, implicaciones y perspectivas para el tratamiento futuro.

Relação entre a doença periodontal e a doença de Alzheimer - Revisão da Literatura / Relationship between periodontal disease and Alzheimer disease ­ literature review

O objetivo do presente estudo foi revisar a literatura para buscar evidências na associação entre a doença de Alzheimer e a Periodontite. A metodologia usada resultou numa busca às bases de dados PubMed/MEDLINE, Cochrane Library e Web of Science, através dos artigos publicados entre o período de maio de 2000 a maio de 2022. A doença de Alzheimer (DA) é classificada como uma condição neurodegenerativa, um grupo heterogêneo de doenças caracterizadas pela perda lenta e progressiva de uma ou mais funções do sistema nervoso. A doença periodontal (DP) é uma doença infecciosa e inflamatória que causa principalmente destruição óssea alveolar e perda dentária e estima-se que entre 20 e 50% da população geral possa sofrer de DP, dos quais 15-20% apresentam formas graves. A inflamação desempenha um papel crítico no aparecimento e progressão de ambas as doenças. A conclusão desta revisão é que a literatura estudada mostra que os patógenos periodontais e as citocinas pró-inflamatórias contribuíram para a progressão do processo neurodegenerativo da doença de Alzheimer. Porém, são necessários mais estudos clínicos controlados randomizados para a confirmação da relação causal desta associação.

The aim of this study was to review the literature to look for evidence in the association between Alzheimer's disease and Periodontitis. The methodology used resulted in a search of the PubMed/MEDLINE, Cochrane Library and Web of Science databases, through the articles published between May 2000 and May 2022. Alzheimer's disease (AD) is classified as a neurodegenerative condition, a heterogeneous group of diseases characterized by the slow and progressive loss of one or more functions of the nervous system. Periodontal disease (PD) is an infectious and inflammatory disease that mainly causes alveolar bone destruction and tooth loss and it is estimated that between 20 and 50% of the general population may suffer from PD, of which 15-20% present severe forms. Inflammation plays a critical role in the onset and progression of both diseases. The conclusion of this review is that the literature studied shows that periodontal pathogens and pro-inflammatory cytokines contributed to the progression of the neurodegenerative process of Alzheimer's disease. However, more randomized controlled clinical trials are needed to confirm the causal relationship of this association.

The contribution of Alois Alzheimer and Oskar Fischer to the understanding of Pick's complex - (Historical Note) / A contribuição de Alois Alzheimer e Oskar Fischer para a compreensão do complexo de Pick - (Nota Histórica)

Arnold Pick described a series of cases with progressive aphasia, behavioural disorders, and dementia. The post-mortem examination revealed on macroscopy, beside diffuse brain atrophy, also circumscribed (lobar) atrophy of the temporal and/or frontal lobes. The histopathology was not provided. Such kind of cases were soon named after the author, being known for a time as 'Pick's disease', coming to constitute a new nosological group. A time later after the original description, Alois Alzheimer and Oskar Fischer completed microscopic examination of similar cases, where the first author found, on silver impregnation, spheric neuronal inclusions, he named 'argentophilic ball' inclusions, while the second one identified complex cortical changes he named 'spongiform cortical wasting', and additionally a type of swollen cell that was named 'ballooned neuron'. Such microscopic changes became the first histopathological markers of this group of diseases.

Arnold Pick descreveu uma série de casos apresentando, de modo progressivo, afasia, transtornos de comportamento e demência. O exame pós-morte revelou à macroscopia, além de atrofia cerebral difusa, também atrofia circunscrita (lobar) dos lobos temporais e/ou frontais. A histopatologia não foi fornecida. Tal tipo de casos foi logo denominado segundo o autor, sendo conhecido por um período como 'doença de Pick', vindo a constituir um novo grupo nosológico. Algum tempo após a discrição original, Alois Alzheimer e Oskar Fischer perfizeram exame microscópio de casos semelhantes, onde o primeiro autor encontrou inclusões neuronais esféricas à impregnação pela prata, que denominou de 'bola argirofílica', enquanto o segundo identificou alterações corticais complexas às quais denominou 'perda cortical espongiforme', além de um tipo de célula tumefeita que chamou de 'neurônio balonizado'. Tais alterações microscópicas tornaram-se os primeiros marcadores histopatológicos desse grupo de doenças.

Factores de riesgo y biomarcadores de la enfermedad de Alzheimer / Risk factors and biomarkers of Alzheimer's disease

Introducción: La enfermedad de Alzheimer, constituye un problema sanitario y social de gran magnitud; precisa de diagnóstico y terapéutica precoces. Se realizó una búsqueda de artículos sobre factores de riesgo y biomarcadores de la enfermedad en las bases de datos PubMed/Medline, Scopus, Scielo y Lilacs, y mediante el buscador Google académico; desde el año 2017 hasta el 2023, en idioma español, inglés y portugués. Objetivo: Analizar los factores de riesgo y los biomarcadores de la enfermedad de Alzheimer. Desarrollo: Los principales factores de riesgo encontrados son edad avanzada, menor educación, poca actividad física, hábito de fumar, consumo excesivo de alcohol, hipertensión arterial, diabetes, obesidad, depresión, pérdida o disminución de la audición, aislamiento social, los traumas craneales y la contaminación ambiental. Los biomarcadores fundamentales son: los marcadores que se utilizan en los estudios de neuroimágenes como la PET Amiloide, PET tau, PET FDG; y en LCR y plasma: Aß42, Aß42/Aß40, p tau 217, p tau 181, GFAP, y neurofilamentos de cadena ligeras. Conclusiones: Se requieren estudios longitudinales, a partir de la presencia de los factores de riesgo asociados a biomarcador, desde edades pregeriátricas en pacientes sanos, que tengan como salidas el deterioro cognitivo y el desarrollo de la demencia, para construir un modelo de predicción(AU)

Introduction: Alzheimer's disease is a health and social problem of great magnitude; it requires early diagnosis and therapy. A search for articles on risk factors and biomarkers of the disease was conducted; in the databases PubMed/Medline, Scopus, Scielo and Lilacs, and through the Google scholar search engine; from 2017 to 2023, in Spanish, English and Portuguese. Objective: To analyze the risk factors and biomarkers of Alzheimer's disease. Development: The main risk factors found are advanced age, lower education, little physical activity, smoking, excessive alcohol consumption, high blood pressure, diabetes, obesity, depression, hearing loss or decrease, social isolation, head trauma and environmental pollution. The fundamental biomarkers are: markers used in neuroimaging studies such as amyloid PET, tau PET, FDG PET; and in CSF and plasma: Aß42, Aß42/Aß40, p tau 217, p tau 181, GFAP, and light chain neurofilaments. Conclusions: Longitudinal studies are required, based on the presence of risk factors associated with biomarkers, from pregeriatric ages in healthy patients, which have cognitive impairment and the development of dementia as outputs, to build a prediction model(AU)

FNDC5/Irisin in dementia and cognitive impairment: update and novel perspective

Epidemiological surveys show that the incidence of age-related dementia and cognitive impairment is increasing and it has been a heavy burden for society, families, and healthcare systems, making the preservation of cognitive function in an increasingly aging population a major challenge. Exercise is beneficial for brain health, and FDNC5/irisin, a new exercise-induced myokine, is thought to be a beneficial mediator to cognitive function and plays an important role in the crosstalk between skeletal muscle and brain. This review provides a critical assessment of the recent progress in both fundamental and clinical research of FDNC5/irisin in dementia and cognitive impairment-related disorders. Furthermore, we present a novel perspective on the therapeutic effectiveness of FDNC5/irisin in alleviating these conditions.

New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes / Nuevos SNP candidatos para la asociación genética con la enfermedad de Alzheimer: un análisis de desequilibrio de ligamiento para los genes FCGRIIB y PILRA

BACKGROUND: Two new SNPs have been recently associated to Alzheimer's disease in African American populations: FCGRIIB rs1050501 C/T, and PILRA rs1859788 A/G. The risk of Alzheimer's disease in FCGRIIB C and PILRA A allele carriers is three times higher than in non-carriers. However, the association between these and other single nucleotide polymorphisms (SNPs) has not been assessed. METHODS: Linkage disequilibrium analysis, with r= 0.8 as a threshold value, was used to impute new candidate SNPs, on genomic data from both genes in 26 populations worldwide (n= 2504) from the 1000Genomes database. RESULTS: Four SNPs (rs13376485, rs3767640, rs3767639 and rs3767641) were linked to rs1050501 and one (rs2405442) to rs1859788 in the whole sample. CONCLUSIONS: Five novel SNPs could be associated with Alzheimer's disease susceptibility and play a causal role, even if none of them are exon variants since their potential roles in the regulation of gene expression.

ANTECEDENTES: Recientemente se han asociado dos nuevos polimorfismos de un solo nucleótido (SNP) a la enfermedad de Alzheimer en poblaciones afroamericanas: FCGRIIB rs1050501 C/T, y PILRA rs1859788 A/G. El riesgo de enfermedad de Alzheimer en los portadores de los alelos FCGRIIB C y PILRA A es tres veces mayor que en los no portadores. Sin embargo, no se ha evaluado la asociación entre estos y otros SNP. MÉTODOS: Se utilizó el análisis de desequilibrio de ligamiento, con r2= 0,8 como valor umbral, para imputar nuevos SNPs candidatos, sobre datos genómicos de ambos genes en 26 poblaciones de todo el mundo (n= 2504) de la base de datos 1000Genomes. RESULTADOS: Cuatro SNPs (rs13376485, rs3767640, rs3767639 y rs3767641) se vincularon al rs1050501 y uno (rs2405442) al rs1859788 en toda la muestra. CONCLUSIONES: Cinco nuevos SNP podrían estar asociados con la susceptibilidad a la enfermedad de Alzheimer y desempeñar un papel causal, aunque ninguno de ellos sea una variante de exón, dado su papel potencial en la regulación de la expresión génica.

Alteraciones genéticas asociadas a la enfermedad de Parkinson y Alzheimer: evolución y respuesta al tratamiento / Genetic Alterations Associated with Parkinson's and Alzheimer's Disease: Evolution and Response to Treatment

La enfermedad de Parkinson y Alzheimer son las enfermedades neurodegenerativas más frecuentes a nivel mundial. Tienen etiología multifactorial, entre ellas, la genética; y son motivo de interés en la investigación científica actual. Se realizó una revisión narrativa con el objetivo de determinar las alteraciones genéticas asociadas a estas patologías, además su influencia en la evolución y respuesta al tratamiento de ellas. Se consultaron artículos originales, revisiones bibliográficas, sistemáticas, metaanálisis en inglés y español, con fecha de publicación entre el 1 enero de 2018 y el 20 de mayo de 2023, en bases como PubMed y Medline. Se utilizaron los términos MeSH «Alzheimer Disease¼, «Parkinson Disease¼, «Drug Therapy¼ y «Mutations¼. El riesgo hereditario para la enfermedad de Parkinson suele ser poligenético, sin embargo, existen genes relacionados con mutaciones monogénicas. Se identifican alteraciones en genes de α-sinucleína, glucocerebrosidasa y quinasa 2 rica en leucina que se relacionan con mayor riesgo de desarrollar Parkinson, además de variaciones en el cuadro clínico y edad de inicio de síntomas. En cuanto a la enfermedad de Alzheimer, las alteraciones en los genes de la proteína precursora amiloide, presenilina 1 y 2 se relacionan con la forma familiar de la enfermedad; por otra parte, las de apolipoproteína E4 se han identificado en la forma esporádica, por lo que se consideran como el factor de riesgo genético más importante para su desarrollo

Parkinson's and Alzheimer's are the most frequent neurodegenerative diseases worldwide. They have a multifactorial etiology, including genetics, and are of interest in current scientific research. A narrative review was carried out with the aim of determining the genetic alterations associated with these pathologies, as well as their influence on their evolution and response to treatment. Original articles, literature reviews, systematic reviews, meta-analyses in English and Spanish, with publication date between January 1, 2018 and May 20, 2023, were consulted in databases such as PubMed and Medline. MeSH terms "Alzheimer Disease", "Parkinson Disease", "Drug Therapy" and "Mutation" were used. Hereditary risk for Parkinson's disease is usually polygenetic, however, there are genes related to monogenic mutations. Alterations in α-synuclein, glucocerebrosidase and leucine-rich kinase 2 genes have been identified that are related to an increased risk of developing Parkinson's disease, in addition to variations in the clinical picture and age of symptom onset. As for Alzheimer's disease, alterations in the genes of the amyloid precursor protein, presenilin 1 and 2 are related to the familial form of the disease; on the other hand, those of apolipoprotein E4 have been identified in the sporadic form, and are therefore considered to be the most important genetic risk factor for its development

Ayuno intermitente y restricción calórica como tratamiento coadyuvante en enfermedad de Alzheimer y esclerosis múltiple / Intermittent Fasting and Caloric Restriction as an Adjunctive Treatment in Alzheimer's Disease and Multiple Sclerosis

Las enfermedades de Alzheimer y esclerosis múltiple son neurodegenerativas, con tratamientos complejos y de costos elevados, orientados a disminuir la progresión de la sintomatología. Sin embargo, a causa de la falta de terapias adecuadas y de los posibles efectos adversos ocasionados por tratamientos de primera línea, es necesario implementar mejores abordajes terapéuticos complementarios que no produzcan mayores efectos secundarios y mejoren la sintomatología de dichas patologías. La restricción calórica y el ayuno intermitente han demostrado ser estrategias novedosas y beneficiosas en enfermedades neurodegenerativas, a través de mecanismos inmunitarios, metabólicos y fisiológicos. Con el objetivo de determinar el uso del ayuno intermitente y la restricción calórica como tratamiento coadyuvante en esclerosis múltiple y enfermedad de Alzheimer, se realizó una revisión narrativa de artículos originales en revistas científicas, en idiomas inglés y español, de 2018 a 2022. El uso de la restricción calórica y ayuno intermitente han generado cambios positivos produciendo disminución de estados proinflamatorios, estrés oxidativo y envejecimiento. Se consideran abordajes que modulan la progresión de la enfermedad y mejoran la función cognitiva por vías de señalización de monofosfato de adenosina cinasa, factor de crecimiento similar a la insulina y la enzima sirtuina, generando un efecto neuroprotector.

Alzheimer's disease and multiple sclerosis are neurodegenerative disorders with expensive and complex treatments aimed at reducing the progression of symptoms. However, due to the lack of adequate therapies and the possible adverse effects caused by first-line treatments, it's necessary to implement better complementary therapeutic approaches that do not produce major side effects and improve symptoms. Caloric restriction and intermittent fasting have been shown to be novel and beneficial strategies in neurodegenerative diseases, through immune, metabolic, and physiological mechanisms. To determine the use of intermittent fasting and caloric restriction as a new treatment in multiple sclerosis and Alzheimer's disease, a narrative review of original articles in both national and international scientific journals, in English and Spanish languages with no greater obsolescence than five years. The use of caloric restriction and intermittent fasting have generated positive changes, producing a decrease in pro-inflammatory states, oxidative stress, and aging. Approaches that modulate disease progression and improve cognitive function of adenosine monophosphate kinase, insulin-like growth factor, and sirtuin enzyme pathways are considered, generating a neuroprotective effect.

Perfil de seguridad y satisfacción con la combinación fija de memantina-donepezilo en pacientes con diagnóstico de Alzheimer moderado a severo / Safety and satisfaction profile with the fixed combination of memantine-donepezil in patients diagnosed with moderate to severe Alzheimer's disease

Introducción: La enfermedad de Alzheimer es un trastorno neurodegenerativo de inicio insidioso y progresión lenta. Epidemiológicamente representa 60% a 70% de los casos de demencia.Objetivo: Determinar el grado de satisfacción y seguridad con la combinación fija de memantina-donepezilo durante 6 meses.Material y métodos: Se llevó a cabo un estudio observacional, transversal y analítico con base a un diseño de Real World Evidence (RWE), para evaluar la satisfacción del tratamiento a través de preguntas con una escala de Likert para la valoración de la satisfacción de 31 pacientes que recibieron como parte de su tratamiento habitual la combinación fija de memantina + donepezilo una vez al día durante seis meses previos a la aplicación de la escala de satisfacción. La información se recopiló de febrero a noviembre del 2021. Resultados: 60% de los eventos adversos fueron leves, 40% moderados. La tolerabilidad luego de 3 meses fue percibida como muy buena o excelente por 81% de pacientes. A seis meses 87,1% calificó como muy bueno o excelente el tratamiento. Satisfacción con el tratamiento a 3 meses fue, "satisfecho en su mayoría" o "totalmente satisfecho" para el 87,1%. Discusión: Prevalencia en el género femenino de 77,4% mayor a la reportada para todo el país de 54,8%, comorbilidades reportadas similares a las descritas por la literatura. Tolerabilidad calificada como excelente en comparación con otros estudios que calificaron como buena tolerabilidad. Conclusión: La administración de la combinación fija de memantina 14 mg + donepezilo 10 mg o memantina 28 mg + donepezilo 10 mg, fue una opción segura y bien tolerada.

Introduction:Alzheimer's disease is a neurodegenerative disorder of insidious onset and slow progression. Epidemiologically it accounts for 60% to 70% of cases of dementia.Objective:Determine the degree of satisfaction and safety with the fixed combination of memantine-donepezil for 6 months.Materials and methods: A cross-sectional, observational, and analytical study was conducted based on a Real World Evidence (RWE) design to assess treatment satisfaction through Likert-scale questions of 31 patients who, as part of their regular treatment, received the fixed combination of memantine + donepezil once daily for six months before the administration of the satisfaction scale. Data collection took place from February to November 2021.Results: 60% of adverse events were mild, 40% moderate. Tolerability after 3 months was perceived as very good or excellent by 81% of patients. At six months 87,1% rated the treatment as very good or excellent. Satisfaction with treatment at 3 months was, "mostly satisfied" or "totally satisfied" for 87,1%. Discussion: Prevalence in the female gender of 77,4% higher than that reported for the whole country of 54,8%, reported comorbidities similar to those described in the literature. Tolerability rated as excellent compared to other studies which rated as good tolerability. Conclusions:Administration of the fixed combination of memantine 14 mg + donepezil 10 mg or memantine 28 mg + donepezil 10 mg was a safe and well-tolerated option.

Effects of Aβ receptor PirB on mouse astrocyte proliferation and reactive astrogliosis / 解放军医学杂志

Objective To observe the effects of amyloid-β(Aβ)receptor PirB on mouse astrocyte proliferation and reactive astrogliosis in vitro.Methods Mouse primary astrocytes were cultured,and divided into control group,Aβ group,Aβ+0.2 μmol/L PEP group,Aβ+0.4 μmol/L PEP group,Aβ+Fluspirilene group,Aβ+GFP-LV group,and Aβ+mPirB-LV group.The mouse astrocytes were treated with soluble PirB extracellular peptide PEP or PirB inhibitor Fluspirilene,respectively,to inhibit endogenous PirB receptor,or overexpressed PirB gene via lentivirus transfection and then treated with Aβ1-42 oligomers.The proliferation of astrocytes was observed by RTCA and EdU methods,and the mRNA expression levels of S-100 calcium-binding protein B(S-100β),Vimentin,Nestin and amyloid precursor protein(APP)associated with reactive astrogliosis of astrocytes were observed by real-time PCR,and the expression level of glial fibrillary acid protein(GFAP)was detected by Western-blotting.Results The results of RTCA monitoring showed that normalized cell index(NCI)values of each group decreased sharply after treatment,and then increased gradually and tended to be stable.The results of EdU staining showed that the proliferative activity of astrocytes was significantly enhanced in the Aβ group(P<0.05)compared with control group;Compared with Aβ group,cell proliferation activity in Aβ + 0.2 μmol/L PEP group,Aβ+0.4 μmol/L PEP group and Aβ+Fluspirilene group were significantly decreased(P<0.01 or P<0.001).The results of real-time PCR showed that compared with control group,mRNA expressions of GFAP,S-100β,Vimentin,Nestin,APP and PirB in Aβ group were significantly increased(P<0.05);Compared with Aβ group,mRNA expressions of GFAP,S-100β,Vimentin,Nestin,APP and PirB in Aβ+0.4 μmol/L PEP group were significantly decreased(P<0.01);Compared with Aβ+GFP-LV group,mRNA expressions of GFAP,S-100β,Vimentin,Nestin,APP and PirB in Aβ +mPirB-LV group were significantly increased(P<0.05).The results of Western blotting showed that compared with control group,the expression of GFAP in Aβ group was significantly increased(P<0.05);Compared with Aβ group,the expression of GFAP in Aβ+0.4 μmol/L PEP group was significantly decreased(P<0.05).Conclusions PirB is an upstream molecule which could regulate astrocyte proliferation and reactive astrogliosis,and inhibiting PirB receptor in astrocytes may be a potential treatment for Alzheimer's disease.

Effects and Mechanisms of Xueshuantong on the Cognitive Function and Abnormal Neural Excitability in Mice with Alzheimer's Disease / 昆明医科大学学报

Objective To explore the possible effects and the underlying molecular mechanisms of xueshuantong[The main active component is panax notoginseng(PNS)]on the cognitive function and neural excitability of mice with Alzheimer's disease(AD).Methods The APP/PS1 mice were used as an animal model for AD research,at the stage when amyloid protein was not detected in mice(2 months of age).Mice in the xueshuantong group(APP/PS1+PNS)were administered by gavage once a day at a dose of 60 mg/kg for six months(for 8 months of age).The mice of the control group were given 0.9%sodium chloride(APP/PS1+Vehicle)intragastric treatment of the same volume,while the wild-type mice of the same age were given 0.9%sodium chloride intragastric treatment as the normal control group(WT+Vehicle)(15 mice in each group,n=15).After six months,the cognitive function of the mice was evaluated by the Novel Object Recognition(NOR)task and Morris Water Maze(MWM)test.The activity of BACE1,the distribution and expression of Nav1.1α,as well as the expression and enzymatic hydrolysis of Navβ2(Navβ2 full-length and Navβ2-CTF fragments)in cortex and hippocampus were detected by EEG,Western blot and cell surface biotinylation assay,respectively.Results The NOR task showed that compared with the mice in the APP/PS1+Vehicle group,the Discrimination index(DI)of mice in the APP/PS1 group was significantly increased after xueshuantong administration(P<0.05).The MWM test found that,the escape latency of the mice in the xueshuantong group was shortened followed six months in gastric administration(P<0.05),while the stay time in the target quadrant and the number of platforms significantly increased(P<0.05)after the removal of the platform.The results of EEG recording showed that xueshuantong reduced the frequency of spike-wave discharges in APP/PS1 mice(P<0.05).Furthermore,xueshuantong significantly reduced the expression of BACE1(P<0.05).In the APP+PNS group,the expression of Navβ2 full-length was increased(P<0.05),as well as corrected the abnormal distribution of Nav1.1α inside and outside of neurons(P<0.05).Conclusion Treatment with xueshuantong can significantly improve the learning and memory ability and correct the abnormal excitability of the brain in AD model mice.The mechanism may be related to the inhibition of BACE1 activity,the reduction of APP/PS1-induced excessive enzyme digestion of Navβ2,the correction of the abnormal expression and distribution of Nav1.1α in cortical and hippocampal neurons,as well as the subsequent regulation of neuronal excitability.

Efficacy Evaluation and Mechanism Research of Qi-Shen-Yi-Zhi Formula in Improving the Learning and Memory Ability of Aβ1-42 Hippocampus Injection Mice / 世界科学技术-中医药现代化

Objective Evaluation of the effect and mechanism research of Qi-Shen-Yi-Zhi formula on improving learning and memory ability in mice injected with Aβ1-42 in hippocampus.Methods Alzheimer's disease model mice were constructed by injecting β amyloid peptide 1-42 into hippocampus and treated with water extracts of Qi-Shen-Yi-Zhi formula.The cognitive abilities of mice were assessed using Morris water maze and Y maze tests,which measure learning and memory capabilities.HE staining was used to observe the damage and TUNEL method was used to determine apoptosis of hippocampus.Detection of the expression of oxidative factors,inflammatory factors,and related antioxidant proteins and apoptotic proteins in the hippocampal tissue of a mouse model of dementia.Results Both high-dose and low-dose groups of Qi-Shen-Yi-Zhi formula significantly improved cognitive dysfunction in mice injected with Aβ1-42 in hippocampus,and attenuated the damage and apoptosis of the hippocampus.It also inhibited oxidative stress and downregulated the expressions of inflammatory factors IL-6,IL-1β and TNF-a,increased the expression of antioxidant proteins Nrf2 and HO-1,and regulated the expressions of apoptotic proteins Caspase-9,Caspase-3,Bax and Bcl-2.Conclusion Qi-Shen-Yi-Zhi formula improves the learning and memory abilities of mice injected with Aβ1-42 in hippocampus,which might be related to the attenuation of oxidative stress and neuronal inflammation of hippocampus.

To Explore the Effect and Mechanism of Shenghui Granule on EC and CA1 Regions of AD Model Rats Based on p38 MAPK Signal Pathway / 世界科学技术-中医药现代化

Objective To observe the effect of Shenghui Granule on EC and CA1 regions of scopolamine-induced dementia rats and explore its mechanism based on p38 MAPK signal pathway.Methods 40 SD rats were randomly divided into four groups(blank group,model group,Shenghui granule group,donepezil group),and were treated with scopolamine.Morris water maze and open field test were used to evaluate the cognition and anxiety behavior of rats.The nerve injury of EC and CA1 was observed by HE staining.The activity of neurons in EC and CA1 regions was observed by c-Fos immunofluorescence staining.Western blot was used to detect p38 MAPK pathway related proteins.Results The behavioral experiment found that Shenghui Granule could improve the cognitive impairment and anxiety-like behavior of AD model rats.The results of HE staining showed that Shenghui granules had protective effects on EC and CA1 regions.The results of c-Fos immunofluorescence staining showed that Shenghui granules could increase the activity of neurons in EC and CA1 regions.Western blot results showed that Shenghui Granule could down-regulate the expression of Bax,reduce the levels of phosphorylated p38 and Tau,and increase the expression of Bcl-2.Conclusion Shenghui granule has protective effect on EC and CA1 regions of AD model rats,and may play a therapeutic role through p38 MAPK signal pathway.

Serum miR-211 and miR-202 Expression Levels in Alzheimer's Disease Patients and Their Correlation with Cognitive Function,Anxiety and Depression / 现代检验医学杂志

Objective To analyze the expression levels of serum microRNA(miR)-211 and miR-202 in patients with Alzheimer's disease and their correlation with cognitive function,anxiety and depression.Methods A total of 90 patients with Alzheimer's disease admitted to Hebei Yanda Hospital from March 2019 to March 2022 were selected as the research group.According to the Clinical Dementia Rating(CDR)score,the patients were grouped into mild group(n=24),moderate group(n=48)and severe group(n=18).Another 90 healthy individuals who underwent physical examination were collected as the control group.The expression levels of miR-211 and miR-202 in serum were compared.Pearson method and Spearman method were used to analyze serum miR-211 and miR-202 and their correlation with cognitive function,anxiety and depression.Logistic regression analysis was used to analyze the influencing factors of Alzheimer's disease.Results The expression levels of serum miR-211(0.59±0.16,1.01±0.31)and miR-202(0.35±0.10,1.00±0.32)were significantly reduced in the research group and control group,with significant differences(t=11.422,18.393,all P<0.05).Serum miR-211(0.73±0.21,0.62±0.17,0.32±0.08)expression levels,miR-202(0.51±0.15,0.33±0.10,0.19±0.04)expression levels,mini-mental state examination(MMSE)score(22.54±1.41 score,19.35±1.01 score,16.23±1.00 score)and Montreal cognitive assessment(MoCA)score(25.35±2.60 score,18.59±1.32 score,16.59±1.24 score)in the mild,moderate and severe groups gradually decreased,and the differences were statistically significant(F=32.006,46.917,163.048,163.703,all P<0.05).Compared with mild group,the serum miR-211,miR-202,MMSE and MoCA scores of severe group and moderate group were reduced,and the differences were statistically significant(t=3.685～25.375,all P<0.05).The mild,moderate and severe groups had a gradual increase in Hamilton anxiety scale(HAMA)score(12.34±1.27 score,20.59±2.09 score and 31.29±2.19 score)and Hamilton depression scale(HAMD)score(14.35±2.13 score,23.89±2.20 score and 35.35±1.21 score),and the differences were statistically significant(F=496.059,553.939,all P<0.05).According to Pearson correlation analysis,miR-211 was positively correlated with miR-202(r=0.651,P<0.05).According to Spearman correlation analysis,miR-211 and miR-202 were positively correlated with MMSE and MoCA(r=0.539～0.585,all P<0.05)and negatively correlated with HAMA and HAMD(r=-0.651～-0.539,all P<0.05).Logistic regression analysis showed that the low expression of miR-211[OR(95%CI):5.321(1.648～17.180)]and miR-202[OR(95%CI):3.158(1.989～5.012)]were risk factors for Alzheimer's disease(P<0.05).Conclusion The serum expression levels of miR-211 and miR-202 in patients with Alzheimer's disease were reduced,indicating miR-211 and miR-202 were closely related to cognitive function,anxiety and depression.

Research progress of large-scale brain network of Alzheimer's disease based on MRI analysis / 实用医学杂志

With the advent of an aging society,Alzheimer's disease(AD)has gradually become a major ailment affecting the elderly.AD is a neurodegenerative disorder associated with cognitive impairments.In AD patients,brain network connections are disrupted,and their topological properties are also affected,leading to the disintegration of anatomical and functional connections.Anatomical connections can be tracked and evaluated using structural magnetic imaging(MRI)and diffusion tensor imaging(DTI),while functional connections are detected through functional MRI to assess their connectivity status.This review incorporates the findings of previous scholars and summarizes the current research of AD.It mainly discusses the imaging characteristics of large-scale brain network changes in AD patients,so as to provide researchers with scientific and objective imaging markers for AD prediction and early diagnosis,as well as future research.

Single-cell RNA sequencing reveals the heterogeneity of astrocytes / 中国组织工程研究

BACKGROUND:Astrocytes are the most abundant cells in the central nervous system,and various subsets of astrocytes are heterogeneous,performing a variety of special functions.Single-cell RNA sequencing(scRNA-seq)technology developed in recent years has extended our understanding of astrocyte heterogeneity from the perspective of transcriptome profiling. OBJECTIVE:To summarize the heterogeneity of scRNA-seq technology in different time and space,and pathological states and expand our knowledge of astrocyte heterogeneity on both molecular and functional levels. METHODS:The relevant articles on astrocyte heterogeneity and scRNA-seq were searched on PubMed,Elsevier,and CNKI databases.The search terms were"astrocytes,scRNA-seq,heterogeneity,Alzheimer disease,spinal cord injury,multiple sclerosis"in Chinese and English.Finally,74 articles were selected for viewing after screening according to inclusion criteria. RESULTS AND CONCLUSION:scRNA-seq studies related to the heterogeneity of astrocytes have shown that astrocyte is significantly heterogeneous across four aspects:species,developmental stage,central nervous system region,and pathological state.(1)Unique expression of certain genes occurs in astrocytes of different species,and the discovery of species-specific genes is beneficial for the translation of clinical studies.(2)During astrocyte development,differential gene expression emerged in the cellular subtypes identified at each stage,which further refined the cellular lineage of astrocytes and laid the foundation for the study of astrocyte developmental trajectories and mechanisms.(3)The discovery of differential gene expression allows regional localization of different astrocyte subpopulations and assists in the diagnosis and treatment of neurological diseases.(4)Astrocyte heterogeneity revealed by scRNA-seq can provide specific markers at the time of disease diagnosis and identify potential therapeutic targets.(5)The heterogeneity of astrocytes exists in many aspects,interacts with each other and is complex.The mechanisms of its generation,maintenance and transformation remain unclear.At present,molecular research on the single-cell level is still lacking.Linking transcriptionally defined astrocyte subpopulations to cellular activity,behavior and disease markers in real time remains one of the great challenges in the field.

Electroacupuncture intervention on the proliferation and differentiation of hippocampal neurons and oligodendrocytes in Alzheimer's disease model mice / 中国组织工程研究

BACKGROUND:The effect of electroacupuncture on the proliferation and differentiation of hippocampal oligodendrocytes in model mice with Alzheimer's disease remains poorly understood while demyelinating reaction related to oligodendrocytes is a common pathological reaction of Alzheimer's disease. OBJECTIVE:To investigate the effects and mechanism of electroacupuncture stimulation of"Baihui"(GV 20),"Fengfu"(GV 16)and bilateral"Shenshu"(BL 23)in Alzheimer's disease model mice on the proliferation and differentiation of endogenous neural stem cells to neurons and oligodendrocytes. METHODS:Forty 6-week-old SPF APP/PS1 transgenic male Alzheimer's disease model mice were randomly divided into electroacupuncture group(n=20)and Alzheimer's disease model group(n=20).Healthy male C57BL/6J mice of the same age were used as normal controls(n=20).The mice in the electroacupuncture group received electroacupuncture at"Baihui"(GV 20),"Fengfu"(GV 16)and bilateral"Shenshu"(BL 23)for 16 weeks(20 minutes/day and one day off a week).After electroacupuncture,Morris water maze was used to detect the changes of learning and memory function.Immunohistochemistry was utilized to detect hippocampal dentate gyrus β-amyloid senile plaques.The expression of BrdU/NeuN and BrdU/GALC in the hippocampal dentate gyrus was detected by immunofluorescence double labeling.Western blot assay was used to detect the expression levels of neuron specific protein Nestin and oligodendrocyte specific protein GALC in the hippocampus.mRNA and protein levels of Notch1 and Hes1 in the hippocampus were detected by real-time fluorescence quantitative PCR and western blot assay. RESULTS AND CONCLUSION:(1)Compared with the normal control group,the ability of learning and memory in the Alzheimer's disease model group decreased significantly;hippocampal dentate gyrus β-amyloid senile plaques increased significantly(P<0.01);the expression of GALC and Nestin in the hippocampus decreased significantly(P<0.01,P<0.05).(2)Compared with the Alzheimer's disease model group,the learning and memory ability of the electroacupuncture group was significantly increased;β-amyloid senile plaque in the hippocampal dentate gyrus decreased significantly(P<0.01).BrdU/NeuN double labeled positive cells in the hippocampal dentate gyrus and Nestin protein expression in the hippocampus increased significantly(P<0.01,P<0.05);GALC expression in hippocampus increased significantly(P<0.01).The mRNA and protein levels of Notch1 in the hippocampus were significantly increased(P<0.05,P<0.01).The mRNA and protein levels of Hes1 in the hippocampus decreased significantly(P<0.05).(3)These findings indicate that electroacupuncture at"Baihui"(GV 20),"Fengfu"(GV 16)and bilateral"Shenshu"(BL 23)of the Alzheimer's disease model infant mice can promote the proliferation and differentiation of endogenous neural stem cells to neurons and oligodendrocytes,which may be regulated through the Notch1/Hes1 pathway.

Effects of aerobic exercise on adult hippocampal neurogenesis in Alzheimer's disease mice / 中国组织工程研究

BACKGROUND:Exercise improves Alzheimer's disease,dementia,and age-related cognitive abilities.A potential mediator between exercise and these health benefits may be adult hippocampal neurogenesis.Therefore,it is of great significance to explore whether and how exercise affects the adult hippocampal neurogenesis process in Alzheimer's disease mice. OBJECTIVE:To observe the effect of aerobic exercise on adult hippocampal neurogenesis of Alzheimer's disease mice,and to explore whether aerobic exercise can promote their adult hippocampal neurogenesis. METHODS:Three-month-old wild-type(C57BL/6Jnju)and APP/PS1 double transgenic Alzheimer's disease mice were randomly divided into four groups:wild control group,wild exercise group,Alzheimer's disease control group and Alzheimer's disease exercise group,with 20 mice in each group.The control group did not do exercise,and the exercise group did aerobic exercise for 5 months.After exercise intervention,real-time PCR,immunofluorescence and western blot assay were used to detect the expression levels of DCX,Ki67,βIII-tubulin and NeuN in the hippocampal tissue of mice in each group. RESULTS AND CONCLUSION:The expressions of DCX,βIII-tubulin and NeuN in the hippocampal dentate gyrus in the Alzheimer's disease control group were significantly lower than those in the wild control group(P<0.05).The expressions of DCX,Ki67,βIII-tubulin and NeuN were significantly higher in the hippocampal dentate gyrus in the Alzheimer's disease exercise group than those in the Alzheimer's disease control group(P<0.05).It is indicated that long-term aerobic exercise intervention can strengthen the proliferation,migration and differentiation of neurons during adult hippocampal neurogenesis and significantly increase the number of neuronal precursor cells and new neurons in Alzheimer's disease mice.