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1.
Front Immunol ; 12: 749468, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659251

RESUMO

In the last few years, microbial infection and innate immune theories have been proposed as an alternative approach explaining the etiopathogenesis and origin of Alzheimer's disease (AD). Lactoferrin, one of the main antimicrobial proteins in saliva, is an important modulator of immune response and inflammation, and represents an important defensive element by inducing a broad spectrum of antimicrobial effects against microbial infections. We demonstrated that lactoferrin levels in saliva are decreased in prodromal and dementia stages of AD compared with healthy subjects. That finding seems to be specific to cerebral amyloid-ß (Aß) load as such observation was not observed in healthy elderly controls or those subjects with frontotemporal dementia. In the present study, we analysed salivary lactoferrin levels in a mouse model of AD. We observed robust and early reduction of lactoferrin levels in saliva from 6- and 12-month-old APP/PS1 mice. Because saliva is secreted by salivary glands, we presume that deregulation in salivary glands resulting in reduced salivary lactoferrin levels may occur in AD. To test this hypothesis, we collected submandibular glands from APP/PS1 mice, as well as submandibular gland tissue from AD patients and we analysed the expression levels of key components of the salivary protein signalling pathway. A significant reduction in M3 receptor levels was found along with decreased acetylcholine (Ach) levels in submandibular glands from APP/PS1 mice. Similarly, a reduction in M3 receptor levels was observed in human submandibular glands from AD patients but in that case, the Ach levels were found increased. Our data suggest that the ACh-mediated M3 signalling pathway is impaired in salivary glands in AD, resulting in salivary gland dysfunction and reduced salivary lactoferrin secretion.

2.
Alzheimers Res Ther ; 13(1): 150, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488875

RESUMO

BACKGROUND: Aging is associated with declining protective immunity and persistent low-grade inflammatory responses, which significantly contribute to Alzheimer's disease (AD) pathogenesis. Detecting aging-related cerebral vulnerability associated with deterioration of the immune system requires from non-invasive biomarkers able to detect failures in the brain-immunity connection. Reduced levels of salivary lactoferrin (sLF), an iron-binding protein with immunomodulatory activity, have been related to AD diagnosis. However, it remains unknown whether decreased sLF is associated with increased cortical amyloid-beta (Aß) load and/or with loss of cortical integrity in normal aging. METHODS: Seventy-four cognitively normal older adults (51 females) participated in the study. We applied multiple linear regression analyses to assess (i) whether sLF is associated with cortical Aß load measured by 18F-Florbetaben (FBB)-positron emission tomography (PET), (ii) whether sLF-related variations in cortical thickness and cortical glucose metabolism depend on global Aß burden, and (iii) whether such sLF-related cortical abnormalities moderate the relationship between sLF and cognition. RESULTS: sLF was negatively associated with Aß load in parieto-temporal regions. Moreover, sLF was related to thickening of the middle temporal cortex, increased FDG uptake in the posterior cingulate cortex, and poorer memory. These associations were stronger in individuals showing the highest Aß burden. CONCLUSIONS: sLF levels are sensitive to variations in cortical Aß load, structural and metabolic cortical abnormalities, and subclinical memory impairment in asymptomatic older adults. These findings provide support for the use of sLF as a non-invasive biomarker of cerebral vulnerability in the general aging population.


Assuntos
Doença de Alzheimer , Lactoferrina , Idoso , Envelhecimento , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Feminino , Humanos , Tomografia por Emissão de Pósitrons
3.
Angew Chem Int Ed Engl ; 60(35): 19344-19354, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34169618

RESUMO

Multitarget directed ligands (MTDLs) are arising as promising tools to tackle complex diseases. The main goal of this work is to create powerful modulating agents for neurodegenerative disorders. To achieve this aim, we have combined fragments that inhibit key protein kinases involved in the main pathomolecular pathways of Alzheimer's disease (AD) such as tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking for a third action in beta-secretase (BACE1), responsible of ß-amyloid production. We obtained well-balanced MTDLs with in vitro activity in three different relevant targets and efficacy in two cellular models of AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into the long and rather narrow BACE1 catalytic site. Finally, we employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs.

4.
J Alzheimers Dis ; 77(2): 795-806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741824

RESUMO

BACKGROUND: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. OBJECTIVE: The fact that circadian rhythm disruption is closely associated to Alzheimer's disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. METHODS: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-ß stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. RESULTS: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. CONCLUSION: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

5.
Sci Rep ; 10(1): 9391, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523019

RESUMO

In Alzheimer's disease (AD) amyloid-ß (Aß) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking Aß-induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on Aß toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse Aß accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on Aß-induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased Aß accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, Aß administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the Aß-induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as Aß accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Anexina A5/metabolismo , Barreira Hematoencefálica/patologia , Plexo Corióideo/fisiologia , Disfunção Cognitiva/metabolismo , Neurônios/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Animais , Apoptose , Autofagia , Cálcio/metabolismo , Células Cultivadas , Disfunção Cognitiva/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica , Ratos , Ratos Wistar
6.
EBioMedicine ; 57: 102834, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32586758

RESUMO

BACKGROUND: Evidences of infectious pathogens in Alzheimer's disease (AD) brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary lactoferrin (Lf) levels, one of the major antimicrobial proteins, in AD patients. METHODS: To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-ß (Aß) load using amyloid-Positron-Emission Tomography (PET) neuroimaging, in two different cross-sectional cohorts including patients with different neurodegenerative disorders. FINDINGS: The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0•95 (0•911-0•992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET+) versus healthy group, and 0•97 (0•924-1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0•93 (0•876-0•989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from FTD with over 87% sensitivity and 91% specificity. INTERPRETATION: Salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker. FUNDING: Instituto de Salud Carlos III (FIS15/00780, FIS18/00118), FEDER, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (PI2016/01) to E.C.; Spanish Ministry of Economy and Competitiveness (SAF2017-85310-R) to J.L.C., and (PSI2017-85311-P) to M.A.; International Centre on ageing CENIE-POCTEP (0348_CIE_6_E) to M.A.; Instituto de Salud Carlos III (PIE16/00021, PI17/01799), to H.B.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/genética , Lactoferrina/genética , Glândulas Salivares/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Imunidade Inata/genética , Lactoferrina/metabolismo , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X , Proteínas tau/genética
7.
Alzheimers Dement ; 16(8): 1196-1204, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32543760

RESUMO

OBJECTIVE: We aim to explain why salivary lactoferrin (Lf) levels are reduced in patients suffering mild cognitive impairment (MCI) and sporadic Alzheimer's disease (sAD).1 We also will discuss if such Lf decrease could be due to a downregulation of the sAD associated systemic immunity. BACKGROUND: Several non-neurological alterations have been described in sAD, mainly in skin, blood cell, and immunological capacities. We reviewed briefly the main pathophysiological theories of sAD (amyloid cascade, tau, unfolder protein tau, and amyloid deposits) emphasizing the most brain based hypotheses such as the updated tau-related neuron skeletal hypothesis; we also comment on the systemic theories that emphasize the fetal origin of the complex disorders that include the low inflammatory and immunity theories of sAD. NEW/UPDATED HYPOTHESIS: Lf has important anti-infectious and immunomodulatory roles in health and disease. We present the hypothesis that the reduced levels of saliva Lf could be an effect of immunological disturbances associated to sAD. Under this scenario, two alternative pathways are possible: first, whether sAD could be a systemic disorder (or disorders) related to early immunological and low inflammatory alterations; second, if systemic immunity alterations of sAD manifestations could be downstream of early sAD brain affectations. MAJOR CHALLENGES FOR THE HYPOTHESIS: The major challenge of the Lf as early sAD biomarker would be its validation in other clinical and population-based studies. It is possible the decreased salivary Lf in early sAD could be related to immunological modulation actions, but other different unknown mechanisms could be the origin of such reduction. LINKAGE TO OTHER MAJOR THEORIES: This hypothesis is in agreement with two physiopathological explanations of the sAD as a downstream process determined by the early lesions of the hypothalamus and autonomic vegetative system (neurodegeneration), or as a consequence of low neuroinflammation and dysimmunity since the early life aggravated in the elderly (immunosenescence).

8.
Mol Neurobiol ; 57(6): 2887-2888, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32367492

RESUMO

The original version of this article unfortunately contained mistake. The authors found that Fig. 4.B mistakenly displays an incorrect GAPDH image. The authors are truly regretful and apologize for the mistake.

10.
Biomolecules ; 10(4)2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276479

RESUMO

Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Ácido Cinurênico/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Ácido Cinurênico/metabolismo , Masculino , Pessoa de Meia-Idade , Triptofano/líquido cefalorraquidiano , Triptofano/metabolismo
11.
Biochem Pharmacol ; 177: 113954, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251676

RESUMO

The choroid plexus (CP) epithelial cells establish an important blood-brain interface, the blood-cerebrospinal fluid barrier (BCSFB), which constitutes a complementary gateway to the blood-brain-barrier for the entrance of several molecules into the central nervous system (CNS). However, the mechanisms that operate at the BCSFB to regulate the molecular traffic are still poorly understood. The taste signalling machinery, present in many extra-oral tissues, is involved in the chemical sensing of the composition of body fluids. We have identified this pathway in rat CP and hypothesised that it could also be present in the human BCSFB. In this study, we characterised the bitter taste receptors (TAS2Rs) expression profiling in human CP by combining data retrieved from available databases of the human CP transcriptome with its expression analysis in a human CP cell line and immunohistochemistry of human CP sections from men and women. TAS2R4, 5, 14 and 39 expression was confirmed in human CP tissue by immunohistochemistry and in HIBCPP cells by RT-PCR, immunofluorescence and Western blot. Moreover, the presence of downstream effector proteins GNAT3, PLCß2 and TRPM5 was also detected in HIBCPP cells. Then, we demonstrated that HIBCPP cells respond to chloramphenicol via TAS2R39 and to quercetin via TAS2R14. Our findings support an active role of TAS2Rs at the human BCSFB, as surveyors of the bloodstream and CSF compositions. These findings open new avenues for studies on the uptake of relevant compounds for targeted therapies of the CNS.


Assuntos
Barreira Hematoencefálica/metabolismo , Plexo Corióideo/metabolismo , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica/métodos , Receptores Acoplados a Proteínas G/genética , Paladar , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Líquido Cefalorraquidiano/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/sangue , Transdução de Sinais/genética
12.
J Neuroinflammation ; 17(1): 22, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937343

RESUMO

BACKGROUND: The increasing risk of obesity and diabetes among other metabolic disorders are the consequence of shifts in dietary patterns with high caloric-content food intake. We previously reported that megalin regulates energy homeostasis using blood-brain barrier (BBB) endothelial megalin-deficient (EMD) mice, since these animals developed obesity and metabolic syndrome upon normal chow diet administration. Obesity in mid-life appears to be related to greater dementia risk and represents an increasing global health issue. We demonstrated that EMD phenotype induced impaired learning ability and recognition memory, neurodegeneration, neuroinflammation, reduced neurogenesis, and mitochondrial deregulation associated with higher mitochondrial mass in cortical tissues. METHODS: EMD mice were subjected to normal chow and high-fat diet (HFD) for 14 weeks and metabolic changes were evaluated. RESULTS: Surprisingly, BBB megalin deficiency protected against HFD-induced obesity improving glucose tolerance and preventing hepatic steatosis. Compared to wild type (wt), the brain cortex in EMD mice showed increased levels of the mitochondrial biogenesis regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2), a thermogenic protein involved in the regulation of energy metabolism. This agreed with the previously found increased mitochondrial mass in the transgenic mice. Upon HFD challenge, we demonstrated these two proteins were found elevated in wt mice but reported no changes over the already increased levels in EMD animals. CONCLUSION: We propose a protective role for megalin on diet-induce obesity, suggesting this could be related to metabolic disturbances found in dementia through brain endocrine system communications.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Animais , Metabolismo Energético/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo
13.
J Alzheimers Dis ; 71(1): 153-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356205

RESUMO

Oxidative stress plays an essential and early role in the pathophysiology of Alzheimer's disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression.


Assuntos
Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Oxirredução , Idoso , Doença de Alzheimer/sangue , Estudos de Casos e Controles , Catalase/sangue , Disfunção Cognitiva/sangue , Feminino , Glutationa/sangue , Glutationa Peroxidase/sangue , Glutationa Redutase/sangue , Humanos , Masculino , Testes de Estado Mental e Demência , Estresse Oxidativo , Fatores Sexuais , Superóxido Dismutase/sangue
14.
Int J Mol Sci ; 20(3)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759742

RESUMO

In Parkinson's Disease (PD), the peripheral changes in the functional capacity and redox state of immune cells has been scarcely investigated, especially in the early PD stages. Aging is a risk factor for PD, and the age-related impairment of the immune system, based on a chronic-oxidative stress situation, is involved in the rate of aging. We analyzed several functions in isolated peripheral blood neutrophils and mononuclear cells from PD stage 2 patients, and compared the results to those in healthy elderly and adult controls. Several oxidative stress and damage parameters were studied in whole blood cells. The results showed an impairment of the lymphoproliferative response in stimulated conditions in the PD patients compared with age-matched controls, who also showed typical immunosenescence in comparison with adult individuals. Higher oxidative stress and damage were observed in whole blood cells from PD patients (lower glutathione peroxidase activity, and higher oxidized glutathione and malondialdehyde contents). Our results suggest an accelerated immunosenescence in PD stage 2, and that several of the parameters studied could be appropriate peripheral biomarkers in the early stages of PD.


Assuntos
Células Sanguíneas/patologia , Proliferação de Células/fisiologia , Linfócitos/patologia , Estresse Oxidativo/fisiologia , Doença de Parkinson/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Células Sanguíneas/metabolismo , Estudos Transversais , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Malondialdeído/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patologia , Oxirredução , Doença de Parkinson/metabolismo
15.
JMIR Res Protoc ; 8(1): e10941, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30632964

RESUMO

BACKGROUND: The Neurological Disorders in Central Spain, second survey (NEDICES-2) is a population-based, closed-cohort study that will include over 8000 subjects aged ≥55 years. It will also include a biobank. OBJECTIVE: The objective of this study was to evaluate all major aspects of the NEDICES-2 (methods, database, screening instruments, and questionnaires, as well as interexpert rating of the neurological diagnoses) in each one of the planned areas (all of them in central Spain) and to test the possibility of obtaining biological samples from each participant. METHODS: A selection of patients and participants of the planned NEDICES-2 underwent face-to-face interviews including a comprehensive questionnaire on demographics, current medications, medical conditions, and lifestyle habits. Biological samples (blood, saliva, urine, and hair) were also obtained. Furthermore, every participant was examined by a neurologist. RESULTS: In this pilot study, 567 study participants were enrolled (196 from hospitals and 371 from primary care physician lists). Of these 567, 310 completed all study procedures (questionnaires and the neurological evaluation). The study was time-consuming for several primary care physicians. Hence, a few primary care physicians from some areas refused to participate, which led to a reconfiguration of study areas. In addition, the central biobank needed to be supplemented by the biobanks of local Spanish National Health System hospitals. CONCLUSIONS: Population-based epidemiological surveys, such as the NEDICES-2, require a pilot study to evaluate the feasibility of all aspects of a future field study (population selection, methods and instruments to be used, neurological diagnosis agreement, and data collection).

16.
Cell Transplant ; 27(3): 423-437, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29873251

RESUMO

Neurogenesis in the adult hippocampus is a unique process in neurobiology that requires functional integration of newly generated neurons, which may disrupt existing hippocampal network connections and consequently loss of established memories. As neurodegenerative diseases characterized by abnormal neurogenesis and memory dysfunctions are increasing, the identification of new anti-aging drugs is required. In adult mice, we found that melatonin, a well-established neurogenic hormone, and the melatonin analog 2-(2-(5-methoxy-1 H-indol-3-yl)ethyl)-5-methyl-1,3,4-oxadiazole (IQM316) were able to induce hippocampal neurogenesis, measured by neuronal nuclei (NeuN) and 5-bromo-2'-deoxyuridine (BrdU) labeling. More importantly, only IQM316 administration was able to induce hippocampal neurogenesis while preserving previously acquired memories, assessed with object recognition tests. In vitro studies with embryonic neural stem cells replicated the finding that both melatonin and IQM316 induce direct differentiation of neural precursors without altering their proliferative activity. Furthermore, IQM316 induces differentiation through a mechanism that is not dependent of melatonergic receptors (MTRs), since the MTR antagonist luzindole could not block the IQM316-induced effects. We also found that IQM316 and melatonin modulate mitochondrial DNA copy number and oxidative phosphorylation proteins, while maintaining mitochondrial function as measured by respiratory assays and enzymatic activity. These results uncover a novel pharmacological agent that may be capable of inducing adult hippocampal neurogenesis at a healthy and sustainable rate that preserves recognition memories.


Assuntos
Hipocampo/efeitos dos fármacos , Melatonina/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Triptaminas/farmacologia
17.
CNS Drugs ; 32(6): 579-591, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736745

RESUMO

BACKGROUND: Alzheimer's disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer's disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects. OBJECTIVE: The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer's disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer's disease, contributing to the instigation of the disease. METHODS: Lymphoblastoid cell lines from patients with Alzheimer's disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in ß-amyloid-treated neuronal cells. RESULTS: We report here that PGN33 normalized the increased proliferative activity of Alzheimer's disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented ß-amyloid-induced cell death in neuronal cells. CONCLUSION: Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Indazóis/uso terapêutico , Linfócitos/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Receptor CB2 de Canabinoide/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/mortalidade , Doença de Alzheimer/patologia , Animais , Bromodesoxiuridina/metabolismo , Estudos de Casos e Controles , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Feminino , Humanos , Indazóis/química , Indazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor CB2 de Canabinoide/agonistas , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
18.
Mol Neurobiol ; 55(12): 8815-8825, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29603091

RESUMO

Platelets are considered a good model system to study a number of elements associated with neuronal pathways as they share biochemical similarities. Platelets represent the major source of amyloid-ß (Aß) in blood contributing to the Aß accumulation in the brain parenchyma and vasculature. Peripheral blood platelet alterations including cytoskeletal abnormalities, abnormal cytoplasmic calcium fluxes or increased oxidative stress levels have been related to Alzheimer's disease (AD) pathology. Therefore, platelets can be considered a peripheral model to study metabolic mechanisms occurring in AD. To investigate peripheral molecular alterations, we examined platelet protein expression in a cohort of 164 subjects, including mild cognitive impairment (MCI), and AD patients, and healthy aged-matched controls. A two-dimensional difference gel electrophoresis (2D-DIGE) discovery phase revealed significant differences between patients and controls in five proteins: talin, vinculin, moesin, complement C3b and Rho GDP, which are known to be involved in cytoskeletal regulation including focal adhesions, inflammation and immune functions. Western blot analysis verified that talin was found to be increased in mild and moderate AD groups versus control, while the other three were found to be decreased. We also analysed amyloid precursor protein (APP), amyloid-ß 1-40 (Aß40) and 1-42 (Aß42) levels in platelets from the same groups of subjects. Upregulation of platelet APP and Aß peptides was found in AD patients compared to controls. These findings complement and expand previous reports concerning the morphological and functional alterations in AD platelets, and provide more insights into possible mechanisms that participate in the multifactorial and systemic damage in AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/imunologia , Plaquetas/metabolismo , Citoesqueleto/metabolismo , Proteômica/métodos , Idoso , Peptídeos beta-Amiloides/sangue , Estudos de Casos e Controles , Disfunção Cognitiva/sangue , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes
19.
Sci Rep ; 8(1): 4064, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29497142

RESUMO

A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper.

20.
Mol Neurobiol ; 55(9): 7327-7339, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29404958

RESUMO

There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with ß-amyloid (Aß) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aß. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aß plays a key role, as is the case of T2DM.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Memantina/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Comportamento Alimentar , Genótipo , Inflamação/patologia , Insulina/metabolismo , Fígado/patologia , Masculino , Memantina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Obesidade/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Transdução de Sinais
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