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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360951

RESUMO

Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer's disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of ß-amyloid protein (Aß) but also induced Aß efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aß. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aß production and clearing Aß from the brains of AD mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Indometacina/farmacologia , Placa Amiloide/tratamento farmacológico , alfa-Macroglobulinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Humanos , Indometacina/uso terapêutico , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Amiloide/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Regulação para Cima , alfa-Macroglobulinas/genética
2.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202125

RESUMO

Alzheimer's disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology.


Assuntos
Doença de Alzheimer/metabolismo , Melatonina/metabolismo , Neurotransmissores/metabolismo , Transmissão Sináptica , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Monoaminas Biogênicas/metabolismo , Suscetibilidade a Doenças , Humanos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Proteínas tau/metabolismo
3.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203978

RESUMO

Alzheimer's disease (AD) is the major cause of dementia, and affected individuals suffer from severe cognitive, mental, and functional impairment. Histologically, AD brains are basically characterized by the presence of amyloid plaques and neurofibrillary tangles. Previous reports demonstrated that protein kinase CK1δ influences the metabolism of amyloid precursor protein (APP) by inducing the generation of amyloid-ß (Aß), finally contributing to the formation of amyloid plaques and neuronal cell death. We therefore considered CK1δ as a promising therapeutic target and suggested an innovative strategy for the treatment of AD based on peptide therapeutics specifically modulating the interaction between CK1δ and APP. Initially, CK1δ-derived peptides manipulating the interactions between CK1δ and APP695 were identified by interaction and phosphorylation analysis in vitro. Selected peptides subsequently proved their potential to penetrate cells without inducing cytotoxic effects. Finally, for at least two of the tested CK1δ-derived peptides, a reduction in Aß levels and amyloid plaque formation could be successfully demonstrated in a complex cell culture model for AD. Consequently, the presented results provide new insights into the interactions of CK1δ and APP695 while also serving as a promising starting point for further development of novel and highly innovative pharmacological tools for the treatment of AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Caseína Quinase Idelta/metabolismo , Peptídeos/metabolismo , Precursor de Proteína beta-Amiloide/química , Caseína Quinase Idelta/química , Morte Celular , Sobrevivência Celular , Humanos , Simulação de Acoplamento Molecular , Neurônios/metabolismo , Fosforilação , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Ligação Proteica
4.
Theranostics ; 11(14): 6644-6667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093845

RESUMO

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aß) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aß, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aß accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aß plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aß plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aß plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Espectroscopia de Ressonância Magnética , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Doença de Alzheimer/patologia , Animais , Escala de Avaliação Comportamental , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Feminino , Radioisótopos de Flúor , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Gliose/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Inflamação/metabolismo , Locomoção/genética , Locomoção/fisiologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Transgênicos , Receptores Colinérgicos/metabolismo , Tálamo/metabolismo , Tálamo/patologia
6.
Expert Opin Investig Drugs ; 30(8): 797-801, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34162295

RESUMO

INTRODUCTION: Alzheimer's disease is the leading cause of disability and poor health, takes a huge emotional and financial burden on family caregivers, and is costly. Donanemab (LY3002813) is a new monoclonal antibody that uniquely targets Aß(p3-42), a pyroglutamate form of Amyloid-ß (Aß) exclusively found in plaques. AREAS COVERED: The phase 2 trial of donanemab in participants with early symptomatic Alzheimer's disease, TRAILBLAZER-ALZ. Donanemab reduced cerebral plaque but not tau load and only marginally improved the primary outcome of cognition and activities of daily living (p = 0.04) without altering individual measures of these. EXPERT OPINION: In TRAILBLAZER-ALZ, anticholinesterase use was given at the beginning but not the end of the trial, and thus, it is not known whether changes in this or other medicines were involved in the outcome with donanemab. Tau load (measured with flortuacipir PET) may be a biomarker of cognition but was not altered by donanemab. As there is no clear evidence that removing cerebral amyloid plaques with Aß antibodies, such as donanemab, improves cognition and the activities of daily living in Alzheimer's disease, clinical trials with these agents should be abandoned, and more time and money should spend on further investigating the underlying cause of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Atividades Cotidianas , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Cognição/efeitos dos fármacos , Humanos , Placa Amiloide/metabolismo
7.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063708

RESUMO

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aß) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aß is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-ß precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aß1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Estresse Oxidativo/genética , Placa Amiloide/genética , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/patologia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia
8.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
9.
J Alzheimers Dis ; 82(1): 129-147, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33998539

RESUMO

The oldest-old, those 85 years and older, are the fastest growing segment of the population and present with the highest prevalence of dementia. Given the importance of neuroimaging measures to understand aging and dementia, the objective of this study was to review neuroimaging studies performed in oldest-old participants. We used PubMed, Google Scholar, and Web of Science search engines to identify in vivo CT, MRI, and PET neuroimaging studies either performed in the oldest-old or that addressed the oldest-old as a distinct group in analyses. We identified 60 studies and summarized the main group characteristics and findings. Generally, oldest-old participants presented with greater atrophy compared to younger old participants, with most studies reporting a relatively stable constant decline in brain volumes over time. Oldest-old participants with greater global atrophy and atrophy in key brain structures such as the medial temporal lobe were more likely to have dementia or cognitive impairment. The oldest-old presented with a high burden of white matter lesions, which were associated with various lifestyle factors and some cognitive measures. Amyloid burden as assessed by PET, while high in the oldest-old compared to younger age groups, was still predictive of transition from normal to impaired cognition, especially when other adverse neuroimaging measures (atrophy and white matter lesions) were also present. While this review highlights past neuroimaging research in the oldest-old, it also highlights the dearth of studies in this important population. It is imperative to perform more neuroimaging studies in the oldest-old to better understand aging and dementia.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Neuroimagem , Idoso de 80 Anos ou mais , Atrofia/patologia , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Substância Branca/patologia
10.
Nat Commun ; 12(1): 3098, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035282

RESUMO

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Vasos Sanguíneos/metabolismo , Encéfalo/metabolismo , Neovascularização Patológica/genética , Placa Amiloide/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Vasos Sanguíneos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Placa Amiloide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
12.
Nat Commun ; 12(1): 3015, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021136

RESUMO

The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4+) and non-containing (XO4-) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4- microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.


Assuntos
Doença de Alzheimer/metabolismo , Microglia/metabolismo , Fagocitose/fisiologia , Placa Amiloide/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Placa Amiloide/genética , Transcriptoma
13.
J Vis Exp ; (170)2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33938883

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that contributes to 60-70% dementia around the world. One of the hallmarks of AD undoubtedly lies on accumulation of amyloid-ß (Aß) in the brain. Aß is produced from the proteolytic cleavage of the beta-amyloid precursor protein (APP) by ß-secretase and γ-secretase. In pathological circumstances, the increased ß-cleavage of APP leads to overproduction of Aß, which aggregates into Aß plaques. Since Aß plaques are a characteristic of AD pathology, detecting the amount of Aß is very important in AD research. In this protocol, we introduce the immunofluorescent staining method to visualize Aß deposition. The mouse model used in our experiments is 5×FAD, which carries five mutations found in human familial AD. The neuropathological and behavioral deficits of 5xFAD mice are well-documented, which makes it a good animal model to study Aß pathology. We will introduce the procedure including transcardial perfusion, cryosectioning, immunofluorescent staining and quantification to detect Aß accumulation in 5×FAD mice. With this protocol, researchers can investigate Aß pathology in an AD mouse model.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças , Animais , Camundongos Transgênicos , Placa Amiloide/metabolismo , Coloração e Rotulagem
14.
Elife ; 102021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33845942

RESUMO

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aß deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aß plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aß plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aß plaques upon SCFA supplementation, microglia contained less intracellular Aß. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aß deposition likely via modulation of the microglial phenotype.


Assuntos
Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal , Microglia/metabolismo , Placa Amiloide/metabolismo , Doença de Alzheimer/metabolismo , Animais , Feminino , Masculino , Camundongos , Organismos Livres de Patógenos Específicos
15.
J Alzheimers Dis ; 81(2): 517-531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814454

RESUMO

BACKGROUND: Microglia play diverse roles in Alzheimer's disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. OBJECTIVE: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. METHODS: Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining. RESULTS: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. CONCLUSION: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-ß deposition.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Microglia/metabolismo , Placa Amiloide/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Camundongos Transgênicos , Placa Amiloide/patologia , Transcriptoma/fisiologia
16.
J Alzheimers Dis ; 81(3): 1195-1209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33896841

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-ß (Aß) plaques in the kidney. Alterations of transforming growth factor ß (TGFß) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aß. OBJECTIVE: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFß signalization is involved in this effect. METHODS: The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing wild type and AD organs. Alterations of canonical and non-canonical TGFß signaling pathways were followed with PCR, western blot, and immunohistochemistry. RESULTS: Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFß pathways in non-trained mice, while expression levels of signal molecules of both TGFß pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AßPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. CONCLUSION: Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFß signaling plays a role in this phenomenon.


Assuntos
Doença de Alzheimer/patologia , Rim/patologia , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Fibrose/metabolismo , Fibrose/patologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia
17.
Psychopharmacology (Berl) ; 238(8): 2073-2082, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33811504

RESUMO

RATIONALE: Amyloid ß peptide (Aß) triggers a series of pathological events including microglial activation, oxidative stress, and inflammation-causing neuronal death and typical pathological changes in Alzheimer's disease (AD). OBJECTIVES: This study aimed to investigate the therapeutic effects and mechanism of bulbocodin D for AD in vivo. METHODS: In this study, Morris water maze (MWM) analysis was used to detect the cognitive ability of APP/PS1 mice after gavage with bulbocodin D for 2 months. Levels of Aß40, Aß42, IL-1ß, and TNF-α were evaluated by ELISA. Aß plaques and biomarkers of neuroinflammation were also investigated through histological analysis. RESULTS: We established that bulbocodin D significantly improved cognitive deficits in APP/PS1 transgenic mice and reduced the levels of amyloid plaque, Aß40, and Aß42. Bulbocodin D also reduced levels of microglial markers IbA1, GFAP, and antioxidant enzymes and reduced the products of lipid peroxidation and proinflammatory cytokines. CONCLUSION: In summary, the present study provides preclinical evidence that oral bulbocodin D can reduce AD pathology.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Antioxidantes/farmacologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Estresse Oxidativo/fisiologia , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/genética
18.
Nat Commun ; 12(1): 2185, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846335

RESUMO

The function of B cells in Alzheimer's disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aß) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aß plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aß plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFß+ microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Linfócitos B/imunologia , Progressão da Doença , Depleção Linfocítica , Peptídeos beta-Amiloides/metabolismo , Animais , Feminino , Hipocampo/patologia , Humanos , Interleucina-1beta/metabolismo , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Fenótipo , Placa Amiloide/metabolismo , Fator de Crescimento Transformador beta/metabolismo
19.
Molecules ; 26(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806326

RESUMO

Recent evidence suggests that the formation of soluble amyloid ß (Aß) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer's disease (AD). However, understanding the pathophysiological role of such soluble Aß aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aß aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aß oligomers in vitro. In this study, we investigated the in vivo detection of Aß oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aß oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aß oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aß oligomers in the brain.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Curcumina/metabolismo , Modelos Animais de Doenças , Imagem por Ressonância Magnética de Flúor-19/métodos , Placa Amiloide/patologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Animais , Encéfalo/metabolismo , Curcumina/química , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/metabolismo
20.
J Alzheimers Dis ; 80(4): 1687-1704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33720883

RESUMO

BACKGROUND: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. OBJECTIVE: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. METHODS: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-ß (Aß) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aß ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. RESULTS: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. CONCLUSION: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Gliose/metabolismo , Transtornos da Memória/metabolismo , Placa Amiloide/metabolismo , Perda de Dente/complicações , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Gliose/patologia , Gliose/psicologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Transtornos da Memória/patologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/patologia , Placa Amiloide/psicologia , Perda de Dente/patologia
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