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1.
Cells ; 12(3)2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36766827

RESUMO

Mitochondrial activity and quality control are essential for neuronal homeostasis as neurons rely on glucose oxidative metabolism. The ketone body, D-ß-hydroxybutyrate (D-BHB), is metabolized to acetyl-CoA in brain mitochondria and used as an energy fuel alternative to glucose. We have previously reported that D-BHB sustains ATP production and stimulates the autophagic flux under glucose deprivation in neurons; however, the effects of D-BHB on mitochondrial turnover under physiological conditions are still unknown. Sirtuins (SIRTs) are NAD+-activated protein deacetylases involved in the regulation of mitochondrial biogenesis and mitophagy through the activation of transcription factors FOXO1, FOXO3a, TFEB and PGC1α coactivator. Here, we aimed to investigate the effect of D-BHB on mitochondrial turnover in cultured neurons and the mechanisms involved. Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD+/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis. These effects increased neuronal resistance to energy stress. D-BHB also stimulated the autophagic-lysosomal pathway through AMPK activation and TFEB-mediated lysosomal biogenesis. Upregulation of SIRT2, FOXOs, PGC1α and TFEB was confirmed in the brain of ketogenic diet (KD)-treated mice. Altogether, the results identify SIRT2, for the first time, as a target of D-BHB in neurons, which is involved in the regulation of autophagy/mitophagy and mitochondrial quality control.


Assuntos
NAD , Sirtuína 2 , Animais , Camundongos , Ácido 3-Hidroxibutírico/farmacologia , Ácido 3-Hidroxibutírico/metabolismo , Autofagia , Glucose/metabolismo , Corpos Cetônicos/metabolismo , Corpos Cetônicos/farmacologia , Lisossomos/metabolismo , Mitocôndrias/metabolismo , NAD/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 2/metabolismo
3.
J Alzheimers Dis ; 82(s1): S65-S90, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33044183

RESUMO

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder that represents a major and increasing global health challenge. In most cases, the first clinical symptoms of AD are preceded by neuropathological changes in the brain that develop years to decades before their onset. Therefore, research in the last years has focused on this preclinical stage of AD trying to discover intervention strategies that might, if implemented effectively, delay or prevent disease progression. Among those strategies, mind-body therapies such as yoga and meditation have gained increasing interest as complementary alternative interventions. Several studies have reported a positive impact of yoga and meditation on brain health in both healthy older adults and dementia patients. However, the underlying neurobiological mechanisms contributing to these effects are currently not known in detail. More specifically, it is not known whether yogic interventions, directly or indirectly, can modulate risk factors or pathological mechanisms involved in the development of dementia. In this article, we first review the literature on the effects of yogic practices on outcomes such as cognitive functioning and neuropsychiatric symptoms in patients with mild cognitive impairment and dementia. Then, we analyze how yogic interventions affect different risk factors as well as aspects of AD pathophysiology based on observations of studies in healthy individuals or subjects with other conditions than dementia. Finally, we integrate this evidence and propose possible mechanisms that might explain the positive effects of yogic interventions in cognitively impaired individuals.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Encéfalo/patologia , Meditação/métodos , Terapias Mente-Corpo/métodos , Yoga , Doença de Alzheimer/psicologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/terapia , Progressão da Doença , Humanos , Meditação/psicologia , Terapias Mente-Corpo/tendências , Yoga/psicologia
4.
Acta Neuropathol ; 137(2): 239-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30426203

RESUMO

Brain accumulation and aggregation of amyloid-ß (Aß) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Aß peptides (mainly Aß1-40 and Aß1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by ß- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aß peptides are truncated at the N-terminus, with Aß4-x peptides being particularly abundant. Aß4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aß peptide sequence, which facilitates Aß4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aß4-40 but unchanged levels of Aß1-x peptides. In the 5xFAD mouse model of amyloidosis, Aß4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4-/- knockout background, Aß4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aß species, but Aß4-40 peptides were absent in cultures derived from ADAMTS4-/- mice indicating that the enzyme was essential for Aß4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aß4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aß peptides.


Assuntos
Proteína ADAMTS4/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Oligodendroglia/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Oligodendroglia/patologia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/patologia
5.
Alzheimers Res Ther ; 10(1): 121, 2018 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-30526652

RESUMO

BACKGROUND: The quantification of amyloid-beta (Aß) peptides in blood plasma as potential biomarkers of Alzheimer's disease (AD) is hampered by very low Aß concentrations and the presence of matrix components that may interfere with the measurements. METHODS: We developed a two-step immunoassay for the simultaneous measurement of the relative levels of Aß38, Aß40 and Aß42 in human EDTA plasma. The assay was employed for the study of 23 patients with dementia of the Alzheimer's type (AD-D) and 17 patients with dementia due to other reasons (OD). We examined relationships with the clinical diagnosis, cerebral Aß load as quantified by amyloid-positron emission tomography, apolipoprotein E genotype, Aß levels and Tau protein in cerebrospinal fluid. RESULTS: Preconcentration of plasma Aß peptides by immunoprecipitation substantially facilitated their immunological measurements. The Aß42/Aß40 and Aß42/Aß38 ratios were statistically significantly lower in the AD-D patients than in the OD group. The areas under the receiver operating characteristic curves reached 0.87 for the Aß42/Aß40 ratio and 0.80 for the Aß42/Aß38 ratio. CONCLUSIONS: The measurement of plasma Aß peptides with an immunological assay can be improved by preconcentration via immunoprecipitation with an antibody against the Aß amino-terminus and elution of the captured peptides by heating in a mild detergent-containing buffer. Our findings support the Aß42/Aß40 ratio in blood plasma as a promising AD biomarker candidate which correlates significantly with the validated core biomarkers of AD. Further studies will be needed for technical advancement of the assay and validation of the biomarker findings.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Imunoensaio/métodos , Fragmentos de Peptídeos/sangue , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Imunoprecipitação/métodos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Curva ROC , Reprodutibilidade dos Testes
6.
Acta Neuropathol Commun ; 6(1): 108, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30340518

RESUMO

Alzheimer's disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements. We show that GPNMB levels increase in an age-dependent manner in transgenic AD models showing profound cerebral neuron loss and demonstrate that GPNMB co-localizes with a distinct population of IBA1-positive microglia cells that cluster around amyloid plaques. Our data further indicate that GPNMB is part of a microglia activation state that is only present under neurodegenerative conditions and that is characterized by the up-regulation of a subset of genes including TREM2, APOE and CST7. In agreement, we provide in vitro evidence that soluble Aß has a direct effect on GPNMB expression in an immortalized microglia cell line. Importantly, we show for the first time that GPNMB is elevated in brain samples and cerebrospinal fluid (CSF) of sporadic AD patients when compared to non-demented controls.The current findings indicate that GPNMB represents a novel disease-associated marker that appears to play a role in the neuroinflammatory response of AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/patologia , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Regulação para Cima/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/genética , Animais , Linhagem Celular Transformada , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Microglia/patologia , Mutação/genética , Fragmentos de Peptídeos/farmacologia , Fosfopiruvato Hidratase/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo
7.
Mol Neurobiol ; 54(8): 6542-6555, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27734334

RESUMO

The environmental enrichment (EE) paradigm is regarded as a useful tool to create a physical and intellectual stimulation for laboratory rodents and has been used in a variety of Alzheimer disease (AD) mouse models. However, the results of these studies have been conflicting as EE had inconsistent effects on memory performance, Aß deposition, inflammatory status and other pathological outcomes depending on the AD model. Here, we studied the influence of a lifelong EE on the widely used 5XFAD mouse model, representing the main pathological features of AD. Although 11 months of enriched housing led to an improved survival rate and a partial rescue of motor performance, no beneficial effects in terms of anxiety phenotype, working memory performance, Aß plaque load, Aß1-42 levels, endogenous APP processing and inflammatory status were observed in 5XFAD mice. Concordantly, no changes in expression levels of BACE1 or Aß-degrading enzymes like neprilysin or insulin-degrading enzyme could be detected in active mice. The 5XFAD model develops a relatively fast and aggressive pathology and therefore presents a model for early onset familial AD. Our results suggest that an intervention like EE might be too mild to counteract the fast disease progression seen in this model. Therefore, our data provide evidence that the effects of physical and cognitive stimulation vary depending on the severity of the pathology of the model and therefore might be more beneficial in models developing a milder AD phenotype.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Meio Ambiente , Abrigo para Animais , Memória de Curto Prazo/fisiologia , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos
8.
Front Mol Neurosci ; 9: 62, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27536216

RESUMO

There is ample evidence that physical activity exerts positive effects on a variety of brain functions by facilitating neuroprotective processes and influencing neuroplasticity. Accordingly, numerous studies have shown that continuous exercise can successfully diminish or prevent the pathology of neurodegenerative diseases such as Alzheimer's disease in transgenic mouse models. However, the long-term effect of physical activity on brain health of aging wild-type (WT) mice has not yet been studied in detail. Here, we show that prolonged physical and cognitive stimulation, mediated by an enriched environment (EE) paradigm for a duration of 11 months, leads to reduced anxiety and improved spatial reference memory in C57BL6 WT mice. While the number of CA1 pyramidal neurons remained unchanged between standard housed (SH) and EE mice, the number of dentate gyrus (DG) neurons, as well as the CA1 and DG volume were significantly increased in EE mice. A whole-brain deep sequencing transcriptome analysis, carried out to better understand the molecular mechanisms underlying the observed effects, revealed an up-regulation of a variety of genes upon EE, mainly associated with synaptic plasticity and transcription regulation. The present findings corroborate the impact of continuous physical activity as a potential prospective route in the prevention of age-related cognitive decline and neurodegenerative disorders.

9.
J Alzheimers Dis ; 50(2): 397-409, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26639971

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-ß (Aß) accumulation, extracellular deposition of Aß peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aß in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Transcriptoma , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Transgênicos , Degeneração Neural/patologia , Presenilina-1/genética , Presenilina-1/metabolismo
10.
Cancer Discov ; 5(7): 768-781, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25934076

RESUMO

UNLABELLED: Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5'-untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors. SIGNIFICANCE: Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small-molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Iniciação Traducional da Cadeia Peptídica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Triterpenos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Células HCT116 , Células HeLa , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Alzheimers Dis ; 44(4): 1291-302, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25408216

RESUMO

The deposition of amyloid-ß (Aß) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aß in production and clearance seems to be the reason for an enhanced Aß accumulation. Besides a systematic clearance through the blood-brain barrier, Aß is cleared from the brain by Aß-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aß-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP-/-), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/- mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aß42 as well as region-specific increases in extracellular Aß deposition. Surprisingly, in young mice, a more abundant cortical Aß plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/- mice. Additionally, young 5XFAD/NEP+/- as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aß peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/- mice and might suggest a reciprocal effect between ECE and NEP activities in Aß degradation.


Assuntos
Doença de Alzheimer , Encéfalo/patologia , Regulação da Expressão Gênica/genética , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Neprilisina/deficiência , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Enzimas Conversoras de Endotelina , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Aprendizagem em Labirinto/fisiologia , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neprilisina/genética , Presenilina-1/genética , RNA Mensageiro/metabolismo
12.
Int J Colorectal Dis ; 29(10): 1189-98, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25060218

RESUMO

PURPOSE: The in vitro and in vivo effects of pyrvinium pamoate (PP), a newly identified WNT signaling inhibitor, were evaluated against colon cancer cell lines and primary colon cancer samples. EXPERIMENTAL DESIGN: Antiproliferative activity of PP and its effects on protein and RNA levels of WNT targets were evaluated on adenomatous polyposis coli (APC (mut)) and ß-catenin(mut) cell lines, one WNT(wt) colon cancer cell line, as well as six primary colon cancer samples with mutant APC in vitro. In addition, the effect of PP on the growth of liver metastasis was examined. RESULTS: PP blocked colon cancer cell growth in vitro in a dose-dependent manner with great differences in the inhibitory concentration (IC(50)), ranging from 0.6 × 10(-6) to 65 × 10(-6) mol/L for colon cancer cells with mutations in WNT signaling. In addition, PP demonstrated a cytotoxic effect on primary colon cancer samples. A combined cytotoxic effect of PP with 5-fluorouracil (5-FU) was observed for two cell lines. PP decreased messenger RNA (mRNA) and protein levels of known WNT target genes as c-MYC and thereby led to the induction of p21. PP inhibited the migration of HCT116 colon cancer cells in vitro and decreased tumor growth in vivo after intraportal injection of HCT116 cells in nude mice. CONCLUSIONS: PP displays promising anticancer activity against a broad panel of human colon cancer cell lines, as well as primary colon cancer samples. However, our findings do not demonstrate a predominant cytotoxic effect of PP on colon cancer cells with mutations in WNT signaling.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Compostos de Pirvínio/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Fluoruracila/administração & dosagem , Genes APC/efeitos dos fármacos , Xenoenxertos , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/secundário , Camundongos , Compostos de Pirvínio/administração & dosagem , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
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