Navegando por Palavras-chave "Alzheimer's disease"

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    Adaptação transcultural da escala de avaliação de incapacidade em demência (Disability Assessment For Dementia - DAD)
    (Academia Brasileira de Neurologia - ABNEURO, 2007-09-01) Carthery-goulart, Maria Tereza; Areza-fegyveres, Renata; Schultz, Rodrigo R. [UNIFESP]; Okamoto, Ivan [UNIFESP]; Caramelli, Paulo; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Nitrini, Ricardo; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
    The original version of the Disability Assessment for Dementia (DAD) was translated into Portuguese and back translated to English. The divergences of translation were identified and discussed, resulting in a version that was used in a preliminary investigation for cross-cultural adaptation. The final version was administered to 29 patients with mild to moderate probable Alzheimer's disease. The correlation coefficients of DAD were 0.929 and 0.932 for the inter-examiner and test-retest evaluations respectively. The reliability indexes were also high (Kappa 0.72 p<0.001 inter-examiners and 0.85 p<0.001 test-retest). The Brazilian version of DAD was easy to administer and had good reliability to assess the functional status of demented patients. It will contribute to the follow-up of these patients in our population. Moreover, it can be used in transcultural studies on functional abilities in dementia.
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    Alterações de linguagem nas fases iniciais da doença de Alzheimer
    (Academia Brasileira de Neurologia - ABNEURO, 2005-06-01) Ortiz, Karin Zazo [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Alzheimer disease (AD) is usually associated with cognitive, language and behavioral impairments, which can get more and more serious as the disease progresses. The aim of this study is to verify language disorders in the early stages of this disease. Twelve patients meeting criteria for problable AD were evaluated by the Boston test, and all of them scored more than 23 points on the Mini-Mental State Examination. Data acquired on this language evaluation were compared with the average of normal population data. All patients showed language disorders. Statistical differences were found in visual confrontating naming and auditory comphrension tasks. The patients performed well in writing and reading tasks. We believe that there might have had an interference in the patient's linguistic task performance due to their memory impairment. We could find language impairments in the early stages of AD.
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    Análise dos efeitos da resistência à insulina central sobre o metabolismo de glicose hepático em modelo animal da doença de Alzheimer
    (Universidade Federal de São Paulo, 2022-12-15) Belaunde, Lucas Humberto Zimmermann [UNIFESP]; Caperuto, Luciana Chagas [UNIFESP]; Pereira, Bruno Fiorelini; http://lattes.cnpq.br/7576513512268341; http://lattes.cnpq.br/0144465590218939; http://lattes.cnpq.br/8224014224797640
    O diabetes mellitus (DM) é um distúrbio metabólico amplamente estudado e que aparenta ter uma relação com outras doenças que envolvem o metabolismo energético. Uma destas doenças é a doença de Alzheimer (DA), já que observou-se que pacientes diabéticos poderiam desenvolver um quadro de amnésia e demência muito característicos, relacionando problemas no metabolismo de órgãos periféricos com o Sistema Nervoso Central (SNC). No entanto, não há muito conhecimento sobre o caminho oposto, com relação à influência da DA no funcionamento de órgãos periféricos como, por exemplo, o fígado. O objetivo deste trabalho é verificar se as interferências no SNC, a partir de um modelo de DA, são capazes de modificar o metabolismo de glicose sistêmico e possíveis alterações no fígado. Foi utilizado um modelo de DA induzido pela administração de estreptozotocina (STZ) de maneira intracerebroventricular (i.c.v.), por uma cirurgia estereotáxica em ratos Wistar jovens e de meia-idade. Cada indivíduo foi pesado e teve o seu comprimento nasoanal medido, calculando-se o Índice de Lee. Os animais foram eutanasiados e o tecido hepático foi coletado e pesado. Antes da eutanásia, os animais tiveram as suas glicemias medidas e também passaram pelos testes de tolerância à glicose oral (oGTT) e de tolerância à insulina intraperitoneal (ipITT). O envelhecimento contribuiu para o ganho de peso e aumento de tamanho, mas a STZ reduziu o peso dos animais de meia-idade. Não houve alterações no Índice de Lee ou na glicemia de jejum em nenhum dos grupos. Os resultados do ipITT mostraram que a STZ tornou os animais jovens resistentes à insulina. Os animais de meia-idade também ficaram resistentes, devido aos efeitos do envelhecimento nestes indivíduos. O oGTT indicou que os animais jovens que receberam STZ não desenvolveram intolerância à glicose, mas os de meia-idade sim. Foi observado que o envelhecimento reduziu o peso relativo do fígado em decorrência do ganho de peso e aumento de tamanho observado nestes animais. Os dados histológicos indicaram que a STZ aumentou a área do citoplasma dos hepatócitos dos animais de ambas as idades e aumentou o volume e o diâmetro do núcleo dos animais jovens. O envelhecimento também foi responsável pelo aumento de parâmetros morfométricos específicos no núcleo dos hepatócitos. Na análise da expressão de proteínas, a fosforilação basal das proteínas IRS-1 (em resíduos serina), AKT, STAT3, JAK2, JNK e NF-kB p65 não foram alteradas, assim como as proteínas sinalizadoras de estresse no Retículo Endoplasmático, PERK e BiP. Diante dos resultados obtidos, conclui-se que com o modelo animal utilizado, foi possível observar que a alteração metabólica central causada pela STZ, além do envelhecimento, produziram mudanças em aspectos morfológicos, metabólicos e histológicos de animais de diferentes idades, reforçando a possível relação discutida entre a DA e o DM2.
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    Apolipoprotein A-V gene polymorphism -1131T > C and Alzheimer's disease
    (Ios Press, 2006-12-01) Barbosa, Fabio Augusto Freiria; Labio, Roger Willian de; Rigolin, Valdeci Oliveira Santos [UNIFESP]; Minett, Thaís Soares Cianciarullo [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Smith, Marilia de Arruda Cardoso [UNIFESP]; Payão, Spencer Luiz Marques [UNIFESP]; Fac Med Marilia; Universidade Federal de São Paulo (UNIFESP); Univ Marilia; Univ Sagrado Coracao
    Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly and is also considered a progeroid genetic syndrome. The etiology of AD is complex and the mechanisms underlying its pathophysiology remain to be claritied. It has been suggested that a high serum cholesterol level is a risk factor for (AD), and that some polymorphisms of genes encoding proteins regulating cholesterol metabolism are associated with AD development. APOA5 is a recently discovered apolipoprotein involved primarily with triglyceride JG) metabolism disorder. This study investigates the association of AD with the APOA5 gene - 1131T > C polymorphisms in samples of 106 patients with Alzheimer's disease (AD), 76 elderly healthy controls and 93 young healthy controls. DNA samples were isolated from blood cells, amplified by PCR and digested with Tru11. We observed that the genotype distributions of APOA5 variants were within Hardy-Weinberg equilibrium in all subject samples. Furthermore, chi-square test comparison for genotype distributions and allele frequencies did not reveal any significant difference among the three groups of subjects (P > 0.05). These results support the idea that these variants are not involved as a risk factor for developing AD.
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    Apolipoprotein E genotype is not associated with cognitive impairment in older adults with bipolar disorder
    (Wiley-Blackwell, 2016) Kerr, Daniel Shikanai; Stella, Florindo; Radanovic, Marcia; Aprahamian, Ivan; Bertollucci, Paulo Henrique Ferreira [UNIFESP]; Forlenza, Orestes Vicente
    ObjectivesCognitive decline is part of the long-term outcome for many individuals with bipolar disorder (BD). The epsilon 4 allele (APOE*4) of apolipoprotein E (APOE) is a well-established risk factor for dementia in Alzheimer's disease (AD). However, its contribution to the risk of cognitive deterioration in BD has not yet been determined. Our aim was to analyze the APOE genotype association with cognitive status in a sample of older adults with BD and compare this to the association in individuals with AD, individuals with mild cognitive impairment (MCI), and healthy controls. MethodsParticipants (n=475) were allocated to four groups: individuals with BD (n=77), those with AD (n=211), those with MCI (n=43), and healthy controls (n=144) according to clinical and neuropsychological assessment. APOE was genotyped by real-time polymerase chain reaction. Tukey's honest significant difference test and Pearson's chi-squared test were used to compare diagnostic groups. ResultsSubjects with BD were similar to controls with respect to the distribution of the APOE genotype (p=0.636) and allele frequencies (p=0.481). Significant differences were found when comparing the AD group to the BD group or to controls (APOE genotype: p<0.0002; allele frequencies: p<0.001). APOE*4 was significantly increased in the AD group when compared to the BD group (p=0.031) and controls (p<0.0001). The cognitively impaired BD subgroup (Mini-Mental State Examination below the cutoff score and/or neuropsychological assessment compatible with MCI) had a statistically significant higher frequency of APOE*2 compared to the AD group (p=0.003). ConclusionsAPOE*4 is not associated with the diagnosis of BD and does not impact the occurrence of dementia in BD. Given the distinct clinical and biological features of cognitive impairment in BD, we hypothesized that dementia in BD is unrelated to AD pathological mechanisms.
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    Apolipoprotein E genotype is not associated with cognitive impairment in older adults with bipolar disorder
    (Wiley-Blackwell, 2016) Kerr, Daniel Shikanai; Stella, Florindo; Radanovic, Marcia; Aprahamian, Ivan; Bertollucci, Paulo Henrique Ferreira [UNIFESP]; Forlenza, Orestes Vicente
    ObjectivesCognitive decline is part of the long-term outcome for many individuals with bipolar disorder (BD). The epsilon 4 allele (APOE*4) of apolipoprotein E (APOE) is a well-established risk factor for dementia in Alzheimer's disease (AD). However, its contribution to the risk of cognitive deterioration in BD has not yet been determined. Our aim was to analyze the APOE genotype association with cognitive status in a sample of older adults with BD and compare this to the association in individuals with AD, individuals with mild cognitive impairment (MCI), and healthy controls. MethodsParticipants (n=475) were allocated to four groups: individuals with BD (n=77), those with AD (n=211), those with MCI (n=43), and healthy controls (n=144) according to clinical and neuropsychological assessment. APOE was genotyped by real-time polymerase chain reaction. Tukey's honest significant difference test and Pearson's chi-squared test were used to compare diagnostic groups. ResultsSubjects with BD were similar to controls with respect to the distribution of the APOE genotype (p=0.636) and allele frequencies (p=0.481). Significant differences were found when comparing the AD group to the BD group or to controls (APOE genotype: p<0.0002; allele frequencies: p<0.001). APOE*4 was significantly increased in the AD group when compared to the BD group (p=0.031) and controls (p<0.0001). The cognitively impaired BD subgroup (Mini-Mental State Examination below the cutoff score and/or neuropsychological assessment compatible with MCI) had a statistically significant higher frequency of APOE*2 compared to the AD group (p=0.003). ConclusionsAPOE*4 is not associated with the diagnosis of BD and does not impact the occurrence of dementia in BD. Given the distinct clinical and biological features of cognitive impairment in BD, we hypothesized that dementia in BD is unrelated to AD pathological mechanisms.
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    Apolipoprotein E4 allele and ribosomal genes in Alzheimer's disease
    (Ios Press, 2004-08-01) Tavares, W. M.; Speranca, M. A.; Labio, Roger Willian de; Peres, Clovis de Araujo [UNIFESP]; Okamoto, Ivan Hideyo [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Smith, Marilia de Arruda Cardoso [UNIFESP]; Payão, Spencer Luiz Marques [UNIFESP]; FAMEMA; Universidade Federal de São Paulo (UNIFESP)
    Ribosomal genes are involved in cellular transcription, translation and gene expression modulation process. An association between 28S/18S rRNA ratio levels with apoptosis and aging has been reported. Moulder et al. [22] and Hashimoto et al. [8] showed an association between apolipoprotein E4 allele and neuronal cell apotosis through diverse mechanisms. The apoE 4 allele is considered a late-onset Alzheimer's disease (AD) risk factor associated with AD pathogenesis. We evaluated the association between apoE4 allele genotyping by PCR and rRNA 28S/18S ratio by slot blotting technique using peripheral blood samples of 18 Alzheimer's disease patients, 18 elderly controls and 18 young controls. A rRNA ratio decrease was observed in AD individuals confirming our previous results but this association is independently of the ApoE4 allele genotype. Thus our results pointed that two different mechanisms are involved in the etiology of Alzheimer disease each one leading independently to cell death. Further studies could investigate these factors.
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    Apoptosis induced by A beta 25-35 peptide is Ca2+-IP3 signaling-dependent in murine astrocytes
    (Wiley-Blackwell, 2014-08-01) Oseki, Karen Tubono [UNIFESP]; Monteforte, Priscila Totarelli [UNIFESP]; Pereira, Gustavo José da Silva [UNIFESP]; Hirata, Hanako [UNIFESP]; Ureshino, Rodrigo Portes [UNIFESP]; Bincoletto, Claudia [UNIFESP]; Hsu, Yi-Te; Smaili, Soraya Soubhi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Med Univ S Carolina
    Although the accumulation of the neurotoxic peptide beta-amyloid (A beta) in the central nervous system is a hallmark of Alzheimer's disease, whether A beta acts in astrocytes is unclear, and downstream functional consequences have yet to be defined. Here, we show that cytosolic Ca2+ dysregulation, induced by a neurotoxic fragment (A beta 25-35), caused apoptosis in a concentration-dependent manner, leading to cytoplasmic Ca2+ mobilization from extra-and intracellular sources, mainly from the endoplasmic reticulum (ER) via IP3 receptor activation. This mechanism was related to A beta-mediated apoptosis by the intrinsic pathway because the expression of pro-apoptotic Bax was accompanied by its translocation in cells transfected with GFP-Bax. A beta-mediated apoptosis was reduced by BAPTA-AM, a fast Ca2+ chelator, indicating that an increase in intracellular Ca2+ was involved in cell death. Interestingly, the Bax translocation was dependent on Ca2+ mobilization from IP3 receptors because pre-incubation with xestospongin C, a selective IP3 receptor inhibitor, abolished this response. Taken together, these results provide evidence that A beta dysregulation of Ca2+ homeostasis induces ER depletion of Ca2+ stores and leads to apoptosis; this mechanism plays a significant role in A beta apoptotic cell death and might be a new target for neurodegeneration treatments.
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    Are Major Depressive Disorder and Diabetes Mellitus Amyloidogenic Conditions?
    (Bentham Science Publ Ltd, 2014-01-01) Baskaran, Anusha; Carvalho, Andre F.; Mansur, Rodrigo Barbachan [UNIFESP]; McIntyre, Roger S.; Queens Univ; Univ Hlth Network; Univ Fed Ceara; Universidade Federal de São Paulo (UNIFESP); Univ Toronto
    Major depressive disorder (MDD) and diabetes mellitus (DM) have reciprocal relationship and share common pathophysiological mechanisms in the central nervous system. Depression and diabetes negatively affect cognitive function and are independent risk factors for mild cognitive impairment and Alzheimers disease (AD). It has been hypothesized that alterations in the production and processing of amyloid beta (A beta) may be the principal pathological process in AD. Furthermore, it has been increasingly demonstrated that a long preclinical course precedes AD. A derivative of this observation is the hypothesis that a convergent pathophysiological substrate subserving MDD and DM may promote beta amyloid (A beta) deposition. The present paper will review evidence linking MDD and DM to A beta accumulation, with a particular emphasis on original reports that report on levels of A beta 40, A beta 42 and the A beta 40/42 ratio in plasma, serum, or cerebrospinal fluid of individuals with MDD and DM. The overarching goal herein is to press the point that MDD and DM are amyloidogenic and consequently represent modifiable risk factors for AD in later life. The prognostic intervention and prevention opportunity suggested by this notion is that: 1) increased rates of mood disorders and DM in an aging population will increase the population attributable risk for AD ascribed to these conditions, 2) improved outcomes in mood disorders and DM by effective treating to target may exert a salutary influence on underlying dementia promoting processes, 3) novel and repurposed medications that are capable of normalizing pathophysiological processes in MDD and DM could decrease the vulnerability towards AD.
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    Assessment of sleep satisfaction in patients with dementia due to Alzheimer's disease
    (Elsevier B.V., 2014-12-01) Oliveira, Fabricio Ferreira de [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Chen, Elizabeth Suchi [UNIFESP]; Smith, Marilia de Arruda Cardoso [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Sleep length and architecture are potential markers of progressive cognitive impairment, while neuropsychiatric symptoms and APOE4- haplotypes have been associated with more sleep complaints in patients with dementia due to Alzheimer's disease (AD). in this cross-sectional study, we sought to investigate which factors might be related to sleep satisfaction in patients with AD. A total of 217 consecutive patients with AD were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functional impairment for activities of daily living, caregiver burden, APOE haplotypes, self-reported sleep satisfaction and length of sleep. Statistical comparisons were conducted with significance at p < 0.05. Concerning sleep complaints, 179 patients (82.5%) reported satisfactory sleep, while 38 (17.5%) were Unsatisfied, with no relation to age, sex, APOE haplotypes, obesity, education, marital status, alcohol consumption or smoking found. Length of sleep (p = 0.011) and behavioural symptoms (p = 0.009) had significant associations with sleep satisfaction. Length of sleep was positively correlated with apathy (p = 0.014) and scores on the Clock Drawing Test (p = 0.015), and inversely correlated with anxiety (p = 0.015) and independence for instrumental activities of daily living (p = 0.003). Patients who were treated with memantine (p = 0.02) or anti-psychotics (p < 0.01) had longer duration of sleep. in conclusion, behavioural symptoms had strong associations with sleep satisfaction, which is highly correlated with length of sleep in patients with AD. Functional independence, apathy, anxiety, use of memantine or anti-psychotics, and scores on the Clock Drawing Test were significantly associated with length of sleep in this sample. (C) 2014 Elsevier B.V. All rights reserved.
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    Association analysis between K and-116A variants of butyrylcholinesterase and Alzheimer's disease in a Brazilian population
    (Elsevier B.V., 2013-03-25) Simao-Silva, Daiane Priscila; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Labio, Roger William de; Payão, Spencer Luiz Marques [UNIFESP]; Furtado-Alle, Lupe; Rodrigues Souza, Ricardo Lehtonen; Univ Fed Parana; Universidade Federal de São Paulo (UNIFESP); Sch Med Marilia
    In Alzheimer's disease (AD) a reduction in acetylcholinesterase (AChE) and an increase in butyrylcholinesterase (BChE) activity are observed. K variant (539T) is the most common variant of the BCHE gene and, although controversial, several studies reported association between K variant and AD. Previous results showed that the K variant alone is not capable of diminishing BChE activity, depending on the presence of the -116A variant. Considering that, we conducted a case-control association study using a clinically well defined group of AD patients (n = 82) and age and sex matched control subjects (EC; n = 78) in order to test the association with these variations of BCHE gene in a Brazilian population. the allele, genotype and haplotype frequencies of the K and the -116A variants of BCHE gene were not significantly different between cases and controls. Although not reaching statistical significance, the results suggested that the presence of -116A variant may have a protective effect against AD. the association of the K variant with AD in a controversial manner in different surveys is probably caused by its linkage disequilibrium with -116A that, by reducing BChE activity, potentially increases cholinergic transmission in comparison with usual genotypes. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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    Association of interleukin 1 beta polymorphisms and haplotypes with Alzheimer's disease
    (Elsevier B.V., 2012-06-15) Payão, Spencer Luiz Marques [UNIFESP]; Gonçalves, Gisela Moraes; Lábio, Roger Willian de; Horiguchi, Lie; Mizumoto, Igor; Rasmussen, Lucas Trevizani [UNIFESP]; Pinhel, Marcela Augusta de Souza; Souza, Dorotéia Rossi Silva; Bechara, Marcelo Dib; Chen, Elizabeth Suchi [UNIFESP]; Mazzotti, Diego Robles [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Smith, Marilia de Arruda Cardoso [UNIFESP]; USC; Universidade Federal de São Paulo (UNIFESP); Fac Med Marilia FAMEMA; Fac Med Sao Jose do Rio Preto; Univ Marilia UNIMAR
    Our study aimed to associate IL-1 beta and IL-1RN polyrnorphisms with AD disease in comparison with elderly control group from São Paulo - Brazil. We genotyped 199 Alzheimer's disease (AD) patients, 165 elderly control and 122 young control samples, concerning VNTR (IL-1RN) and -511C>T and -31T>C (IL-1 beta) polymorphisms. Our findings revealed that -511C/-31T/2-repetitions VNTR haplotype had a protective effect for AD when compared to EC (p=0.005), whereas -511C/-31C/1-repetition VNTR haplotype was associated as a risk factor for AD (p=0.021). Taken together, we may suggest that there is a relevant role of IL-1 genes cluster in AD pathogenesis in this Brazilian population. (c) 2012 Elsevier B.V. All rights reserved.
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    Astrocytic Expression of the Immunoreceptor CD300f Protects Hippocampal Neurons from Amyloid-beta Oligomer Toxicity In Vitro
    (Bentham Science Publ Ltd, 2017) Lima, Thiago Zaqueu de [UNIFESP]; Sardinha, Luis Roberto; Sayos, Joan; Mello, Luiz Eugenio Araujo de Moraes [UNIFESP]; Peluffo, Hugo
    Background: Astrocytes contribute to neuroinflammation that accompanies neurodegenerative disorders such as Alzheimer's disease (AD). In this sense, the toxicity of these diseases might be attenuated through the modulation of astrocytic inflammatory responses. Recently, the CD300f immunoreceptor was described as a new member of the CD300 immunoreceptor family, showing promising modulatory properties. Objective: Here, we investigated whether overexpression of hCD300f (the human isoform of CD300f) in astrocytes protects hippocampal neurons against the degeneration induced by amyloid-beta (A beta) oligomer. Method: Astrocyte monolayers were transfected with hCD300f before seeding the hippocampal neurons, and then the co-culture was exposed to A beta(1-42) oligomers (5 mu M, 48h). Results: hCD300f expression significantly abrogated the neuronal loss elicited by A beta. This effect was dependent on neuron-astrocyte cell-cell interactions since no protection was observed using conditioned media from transfected astrocytes. Astrocyte modulation was dependent on the cytoplasmic signaling tail of hCD300f. Furthermore hCD300f expression did not affect the ability of astrocytes to uptake A beta(1-42) oligomers by endocytosis, which discards the possibility that increased A beta(1-42) clearance could mediate neuroprotection by hCD300f. Conclusion: These results suggest that the astrocyte-directed expression of the hCD300f immune receptor can be a neuroprotective strategy in AD disease.
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    Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications
    (Frontiers Media Sa, 2018) Uddin, Md. Sahab; Stachowiak, Anna; Al Mamun, Abdullah; Tzvetkov, Nikolay T.; Takeda, Shinya; Atanasov, Atanas G.; Bergantin, Leandro B. [UNIFESP]; Abdel-Daim, Mohamed M.; Stankiewicz, Adrian M.
    Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid beta (A beta), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of A beta is dysregulated, which leads to the accumulation and aggregation of A beta. Metabolism of A beta and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.
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    Avaliação da associação entre nível sérico de sirtuína 2 e doença de Alzheimer
    (Universidade Federal de São Paulo (UNIFESP), 2017-08-31) Dauar, Marina Tedeschi [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Mazzacoratti, Maria da Graça Naffah [UNIFESP]; http://lattes.cnpq.br/0945751507151552; http://lattes.cnpq.br/0536597854124056; http://lattes.cnpq.br/8285964028431848; Universidade Federal de São Paulo (UNIFESP)
    Introduction: Alzheimer's disease (AD) is the most prevalent form of degenerative dementia and there is no effective treatment to prevent its progression. An important step in the search for a cure is the identification of a biomarker able to diagnose the disease early in the pathological process, at which point a pharmacological intervention would be effective. Sirtuins are proteins present in most living organisms and their functions have been related to the control of healthy longevity, neuroprotection and the pathophysiology of dementia. Sirtuin 1 is altered in the serum and plasma of AD patients representing a potential biomarker for the disease. It has already been showed that the T allele of the rs10410544 polymorphism of the Sirtuin 2 (SIRT2) gene is associated with a greater risk of development of AD, but the potential of SIRT2 as a biomarker of AD needs to be better investigated. Objective: To evaluate the association between serum SIRT2 and AD. Evaluate the impact of SIRT2 on risk factors of AD and the correlation of SIRT2 with clinical parameters of the disease. Methods: we conducted a case-control study, which included patients with AD and controls without cognitive deficit. Clinical information was obtained through medical consultation and clinical and neuropsychological tests. The serum level of SIRT2 was measured by the ELISA method, fasting glucose was measured by colorimetric assay and glycated hemoglobin by HPLC. Results: Thirty patients with AD and 14 subjects without cognitive deficit were included. No difference was found in the level of serum SIRT2 between AD and controls (p = 0.247). The logistic model that used SIRT2 levels to predict whether an individual would be in the case group or control group was not different than 50%. SIRT2 levels showed no difference according to the diagnosis of hypertension, hyperlipidemia, anxiety or depression. SIRT2 levels were not correlated with age, sex, length of evolution and severity of the disease or fasting glucose levels. We found that serum SIRT2 levels were significantly increased in patients with type 2 diabetes compared to non-diabetic patients (p=0.027). There was also a positive correlation between the levels of glycated hemoglobin and SIRT2 (p=0.027). Conclusion: No association was found between serum SIRT2 and AD. The findings suggest a role of SIRT2 on the pathophysiology of type 2 diabetes that deserves to be further investigated.
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    Avaliação da memória do tipo episódica no modelo experimental da Doença de Alzheimer em animais tratados com Extrato Padronizado de Ginkgo biloba
    (Universidade Federal de São Paulo, 2022-07-25) Santana, Jacqueline Gonçalves [UNIFESP]; Cerutti, Suzete Maria [UNIFESP]; http://lattes.cnpq.br/9076343601956182; http://lattes.cnpq.br/8498816936418638
    A memória é um mecanismo biológico fundamental para a vida dos animais e seres humanos, vida em sociedade, tomada de decisões e, no caso de humanos, manter nossa individualidade. A doença de Alzheimer (DA) é caracterizada pelo comprometimento da formação e codificação de novas memórias prejudicando, de maneira precoce, as memórias episódicas. Estudos corroboram que o Diabetes Mellitus pode estar relacionado como um fator de risco para Doença de Alzheimer. Nosso grupo vem demonstrando a capacidade modulatória de substâncias isoladas e/ou compostas, derivadas de plantas, como o extrato padronizado de Ginkgo biloba (EGb) na formação e evocação de memórias de curto e de longo prazo, do tipo episódica. Este estudo avaliou o efeito do tratamento crônico com diferentes doses de EGb (0.25, 0.5 e 1.0 g/kg) na memória de curto e de longo prazo em ratos adultos jovens no modelo da doença de Alzheimer induzido por meio da injeção intracerebroventricular de estreptozotocina (STZ). Foram utilizados ratos Wistar machos de 3-4 meses de idade (pesando 300-350 g) submetidos à tarefa de esquiva discriminativa no labirinto em cruz elevado (do inglês, PM-DAT), que avalia ao mesmo tempo, memória do tipo episódica aversiva, comportamentos do tipo ansioso e atividade motora espontânea. A formação de memória foi avaliada por meio da porcentagem de tempo e de entradas no braço fechado aversivo no treino (short-term memory, STM) e, 24 horas depois, no teste (Long-term memory). Os comportamentos de ansiedade foram avaliados pelo tempo de permanência e porcentagem de tempo no braço aberto, associados a comportamentos de autolimpeza, elevações e de avaliação de risco. Os dados demonstram que a STZ não causou déficit de memória de curto prazo avaliada, entretanto, os dados do teste mostram uma preferência dos animais pelo braço fechado aversivo em relação ao braço fechado não aversivo, o que sugere déficit de memória de longo prazo. O tratamento com EGb na dose de 0,25 g/kg após a injeção de STZ teve um efeito positivo revertendo o déficit de memória verificado. Os dados ainda mostram que o tratamento com EGb, nas três doses (0.25, 0.5 e 1.0 g/kg) reduziram os comportamentos do tipo ansioso
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    Brain-Penetrating Angiotensin-Converting Enzyme Inhibitors and Cognitive Change in Patients with Dementia due to Alzheimer's Disease
    (Ios Press, 2014-01-01) Oliveira, Fabricio Ferreira de [UNIFESP]; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Chen, Elizabeth Suchi [UNIFESP]; Smith, Marilia de Arruda Cardoso [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Controversy over benefits of angiotensin-converting enzyme inhibitors (ACEIs) for treatment of dementia due to Alzheimer's disease (AD) led to this alternative investigational approach by the employment of pharmacogenetic methods, correlating the cognitive change of patients with late-onset AD with the presence of common ACE gene promoter polymorphisms, and stratifying the sample in groups of patients who responded or not to the brain-penetrating ACEIs Captopril or Perindopril. A trend was found for treatment with brain-penetrating ACEIs to slow cognitive decline in AD patients with the haplotype rs1800764 (CC): rs4291 (TT) (p = 0.024), and also non-significantly for independent carriers of rs1800764 or rs4291.
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    Can the rDNA methylation pattern be used as a marker for Alzheimer's disease?
    (Elsevier B.V., 2008-11-01) Speranca, Marcia Aparecida; Batista, Lisandra Mesquita; Lourenco, Ricardo da Silva; Tavares, Wagner Malago; Bertolucci, Paulo Henrique Ferreira [UNIFESP]; Santos Rigolin, Valdeci de Oliveira; Payão, Spencer Luiz Marques [UNIFESP]; Smith, Marilia de Arruda Cardoso [UNIFESP]; Marilia Med Sch; Universidade Federal de São Paulo (UNIFESP)
    Background: Differential methylation activity of the human rDNA in Alzheimer's disease (AD) patients has been demonstrated by classic cytogenetic tools. indicating a decrease in rRNA gene expression. Methylation of CpGs is an important epigenetic mechanism involved in gene expression repression of tandem repeating genes during ageing. Thus, rDNA specific methylation pattern could be involved in AD and be used as a marker of the disease or of its progression.Methods: the methylation pattern of three rDNA regions, including the promoter, 18S, and 28S, was investigated with the use of restriction endonucleases sensitive to methylation and Southern blotting, from DNA extracted from total peripheral blood cells of 28 AD patients and 28 elderly and Young controls.Results: We did not find a significant divergence in the methylation pattern of the Studied regions and in the relative amount of rDNA methylated copies among the individuals' groups.Conclusions: No differential methylation pattern of rDNA genes was observed in total peripheral blood cells in aged and AD subjects by the methodology used. (C) 2008 the Alzheimer's Association, All rights reserved.
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    Caracterização in vitro de neuroesferas e seu potencial de regeneração na doença de alzheimer e lesão por stab wound
    (Universidade Federal de São Paulo (UNIFESP), 2016-03-06) Paiva, Daisylea de Souza [UNIFESP]; Monteiro, Beatriz de Oliveira [UNIFESP]; http://lattes.cnpq.br/0245964878412260; http://lattes.cnpq.br/3693514872706694; Universidade Federal de São Paulo (UNIFESP)
    Objetctive: verify the role of neural stem cells (NSC) in three different aspects: in vitro behaviour, use in memory repair in transgenic animals for Alzheimer's Disease (DA, APPswe/PS1dE9) following transplantation, and expression of proteins related to injury response. Methods: We used in vitro techniques for cell culture of neuroespheres, genome-wide techniques as well as transplantation and behavioral tests. Results: We verified that the APPswe/PS1dE9 transgene affect neurospheres growth rate as well as promoting cellular death. Furthermore, is important to note that differentiated astrocytes from AD animals neurospheres presented hypertrophic morphology, alike the astrocytes from WT animals. Therefore, in this model is possible to identify alterations in NSC as well as soluble amyloid precursor protein secretion during the embrionic stage that can promote proliferation without interfere in the normal development of the animal. When transplanted in transfenic animals for DA, NSCs were able to contribute to neural repair by increasing neurogenesis and secretion of BDNF neurotrophin. Nevertheless there was no effect on memory and habituation in transplanted AD animals. Therefore we demonstrated that even without improving memory at behavioural level, NSC transpantation increased the neurotrophic support in hippocampus and can be responsible for other modifications at molecular level that should be better investigated. From the results of in vitro experiments and to better understand the behaviour of astrocytes in AD we decide to compare the expression pattern of proteins overexpressed at the lesion site of the SW (stab wound). To perform this analysis, we used the genome-wide data from Magdalena Götz's lab to select candidates that could play a role in the stab wound lesion and in AD. Among the top upregulated genes in reactive macroglia (astrocytes and NG2-glia), most of them were related to inflammation and, among these genes we selected four candidates (Osteopontin, CD68 and Galectin-1 and -3). We verified that although they were overexpressed in reactive macroglia after SW injury, the same cells do not express these proteins in AD animals. Whereby SW is an accute injury that is healed within few weeks, we assumed that the downregulation of these proteins could be related to the disease chronicity. Conclusion: By evaluating the in vitro features and role in neurodegeneration processes, we verified that when transplanted, NSC secrete factors that increase the neurotrophic support and during development can play a role in compensating cell death in AD animals. However, in old AD animals macroglial cells do not express proteins that could assist lesion resolution. This work offers insights about the role of NSC and macroglia in Alzheimer's disease.
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    Clinical Dementia Rating independently predicted conversion to dementia in a cohort of urban elderly in Brazil
    (Cambridge Univ Press, 2013-02-01) Marcondes Macedo Montano, Maria Beatriz [UNIFESP]; Andreoni, Solange [UNIFESP]; Ramos, Luiz Roberto [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Background: Dementia is a major public health problem in aging populations. the Clinical Dementia Rating (CDR) classifies the severity of dementia and identifies borderline cases that supposedly have higher rates of conversion to dementia. This study aims to verify the dementia conversion rate (CR) in a subsample of an elderly cohort (70+ free of the disease), and to identify risk factors, determining whether CDR is able to predict which individuals have high likelihood of converting.Methods: A subsample of 156 participants was clinically evaluated for dementia at baseline in which 80 patients without dementia were reassessed after 2.6 years on average to verify the conversion. the CR was analyzed according to demographic, health variables, and CDR classification at baseline, using the Poisson regression method in univariate and multivariate analyses, with exposure time as an offset variable (person-years).Results: From those re-evaluated, 50% had CDR = 0 and a CR of 38.1/1,000 person-years and the other 50%, CDR = 0.5 (70% with sum of boxes scores <= 1, CR = 145.4/1,000 person-years and 30% > 1, CR = 216.8/1,000 person-years). CR was 91.3/1,000 person-years on average. in the multivariate analysis, when compared with those with CDR = 0, the hazard ratio of those with CDR = 0.5 was 3.82; and for those with CDR = 0.5 and sum of boxes scores > 1, 5.69.Conclusions: Conversion rate to dementia was significantly higher among those with CDR = 0.5 and even higher for those whose sum of boxes scores was > 1. Therefore, CDR was able to predict which individuals had a higher likelihood of converting to dementia.