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1.
Sci Adv ; 10(26): eadn5229, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38924414

RESUMO

There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.


Assuntos
Tecido Adiposo Branco , Quimiocina CCL22 , Metabolismo Energético , Linfonodos , Macrófagos , Termogênese , Animais , Feminino , Humanos , Masculino , Camundongos , Adipócitos Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Quimiocina CCL22/metabolismo , Eosinófilos/metabolismo , Linfonodos/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais
2.
Dev Cell ; 59(10): 1233-1251.e5, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38569546

RESUMO

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively explored. Here, through in vivo lineage tracing and mouse modeling, we observed that platelet-derived growth factor receptor beta (PDGFRß)+ pericytes give rise to developmental brown adipocytes but not to those in adult homeostasis. By contrast, T-box 18 (TBX18)+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRß+ pericytes promotes brown adipogenesis by downregulating PDGFRß. Furthermore, inhibition of Notch signaling in PDGFRß+ pericytes mitigates high-fat, high-sucrose (HFHS)-induced glucose and metabolic impairment in mice during their development and juvenile phases. Collectively, these findings show that the Notch/PDGFRß axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.


Assuntos
Adipócitos Marrons , Adipogenia , Diferenciação Celular , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Receptores Notch , Células-Tronco , Animais , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptores Notch/metabolismo , Camundongos , Adipócitos Marrons/metabolismo , Adipócitos Marrons/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Transdução de Sinais , Pericitos/metabolismo , Pericitos/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/citologia , Camundongos Endogâmicos C57BL , Masculino
3.
bioRxiv ; 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37293108

RESUMO

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here through in vivo lineage tracing, we observed that PDGFRß+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRß+ pericytes promotes brown adipogenesis through the downregulation of PDGFRß. Furthermore, inhibition of Notch signaling in PDGFRß+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFRß axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health. Highlights: PDGFRß+ pericytes act as an essential developmental brown APC.TBX18+ pericytes contribute to brown adipogenesis in a depot-specific manner.Inhibiting Notch-Pdgfrß axis promotes brown APC adipogenesis.Enhanced postnatal brown adipogenesis improves metabolic health in adult stage.

4.
Nat Commun ; 14(1): 2731, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37169793

RESUMO

A potential therapeutic target to curb obesity and diabetes is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of cyclin dependent kinase inhibitor 2A (Cdkn2a) as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and male mice confer long-term metabolic protection from diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically, Cdkn2a promotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a ablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Notably, both Cdkn2a and Becn1 exhibit striking positive correlations with adiposity. Hence, blocking Cdkn2a-mediated BECN1 activity holds therapeutic potential to sustain beige adipocytes in treating obesity and related metabolic diseases.


Assuntos
Adipócitos Bege , Tecido Adiposo Bege , Obesidade , Animais , Humanos , Masculino , Camundongos , Adipócitos Bege/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Adiposidade/fisiologia , Obesidade/genética , Obesidade/metabolismo , Termogênese
5.
Proc Natl Acad Sci U S A ; 120(16): e2222084120, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-37040416

RESUMO

Macrophage targeting therapies have had limited clinical success in glioblastoma (GBM). Further understanding the GBM immune microenvironment is critical for refining immunotherapeutic approaches. Here, we use genetically engineered mouse models and orthotopic transplantation-based GBM models with identical driver mutations and unique cells of origin to examine the role of tumor cell lineage in shaping the immune microenvironment and response to tumor-associated macrophage (TAM) depletion therapy. We show that oligodendrocyte progenitor cell lineage-associated GBMs (Type 2) recruit more immune infiltrates and specifically monocyte-derived macrophages than subventricular zone neural stem cell-associated GBMs (Type 1). We then devise a TAM depletion system that offers a uniquely robust and sustained TAM depletion. We find that extensive TAM depletion in these cell lineage-based GBM models affords no survival benefit. Despite the lack of survival benefit of TAM depletion, we show that Type 1 and Type 2 GBMs have unique molecular responses to TAM depletion. In sum, we demonstrate that GBM cell lineage influences TAM ontogeny and abundance and molecular response to TAM depletion.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Camundongos , Animais , Macrófagos Associados a Tumor/metabolismo , Linhagem da Célula , Glioblastoma/patologia , Neoplasias Encefálicas/patologia , Macrófagos/metabolismo , Processos Neoplásicos , Microambiente Tumoral
6.
Dev Cell ; 57(1): 32-46.e8, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35016005

RESUMO

We test the hypothesis that glioblastoma harbors quiescent cancer stem cells that evade anti-proliferative therapies. Functional characterization of spontaneous glioblastomas from genetically engineered mice reveals essential quiescent stem-like cells that can be directly isolated from tumors. A derived quiescent cancer-stem-cell-specific gene expression signature is enriched in pre-formed patient GBM xenograft single-cell clusters that lack proliferative gene expression. A refined human 118-gene signature is preserved in quiescent single-cell populations from primary and recurrent human glioblastomas. The F3 cell-surface receptor mRNA, expressed in the conserved signature, identifies quiescent tumor cells by antibody immunohistochemistry. F3-antibody-sorted glioblastoma cells exhibit stem cell gene expression, enhance self-renewal in culture, drive tumor initiation and serial transplantation, and reconstitute tumor heterogeneity. Upon chemotherapy, the spared cancer stem cell pool becomes activated and accelerates transition to proliferation. These results help explain conventional treatment failure and lay a conceptual framework for alternative therapies.


Assuntos
Sobrevivência Celular/fisiologia , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Ciclo Celular/genética , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Invasividade Neoplásica/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Transcriptoma/genética
7.
Cell Insight ; 1(2): 100015, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37193130

RESUMO

In the past decades, great progress has been made for the prevention and treatment of lung cancer. Yet, lung cancer remains as the leading cause of cancer death worldwide. In this manuscript, we describe the current genetic and molecular characterization of lung cancer subtypes, review up-to-date treatment options for lung cancer patients, summarize the antibodies and small molecule drugs under clinical development, and elaborate on the expression and characteristics of important RTK primary targets and representative preclinical agents which may provide new opportunities for lung cancer treatment. Since gefitinib was first introduced to non-small-cell lung carcinoma (NSCLC) patients in 2002, remarkable progress has been made in targeted therapy for NSCLC patients with the development of multiple generations of small molecule inhibitors targeting relevant driver mutations. However, very little achievement has been made in the development of targeted drugs for small-cell lung carcinoma (SCLC). The successful harness of immune checkpoint inhibitors against PD-1/PD-L1 has marked a major advancement in recent lung cancer treatment. Looking forward, therapeutic strategies that tackle brain metastasis are highly desirable, the combination of molecular testing and strategies tailored to tackle tumor heterogeneity and resistance mechanisms is the key direction for future development.

8.
Mol Cancer Ther ; 20(9): 1521-1532, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34172531

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans. Over the past several decades, despite improvements in neurosurgical techniques, development of powerful chemotherapeutic agents, advances in radiotherapy, and comprehensive genomic profiling and molecular characterization, treatment of GBM has achieved very limited success in increasing overall survival. Thus, identifying and understanding the key molecules and barriers responsible for the malignant phenotypes and treatment resistance of GBM will yield new potential therapeutic targets. We review the most recent development of receptor tyrosine kinase targeted therapy for GBM and discuss the current status of several novel strategies with the emphasis on blood-brain barrier penetration as a major obstacle for small-molecule drugs to achieve their therapeutic goals. Likewise, a major opportunity for the treatment of GBM lies in the use of biomarkers for the discovery and development of new receptor tyrosine kinase targeted therapy.


Assuntos
Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos
9.
Cell Stem Cell ; 28(8): 1397-1410.e4, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34010628

RESUMO

NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve plexiform neurofibromas that originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discover and characterize a rare MPNST cell population with stem-cell-like properties, including quiescence, that is essential for tumor initiation and relapse. Following isolation of these cells, we derive a cancer-stem-cell-specific gene expression signature that includes consensus embryonic neural crest genes and identify Nestin as a marker for the MPNST cell of origin. Combined targeting of cancer stem cells along with antimitotic chemotherapy yields effective tumor inhibition and prolongs survival. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to MPNST therapy development.


Assuntos
Neurofibromatose 1 , Neurofibrossarcoma , Animais , Modelos Animais de Doenças , Camundongos , Recidiva Local de Neoplasia , Neurofibromatose 1/genética
10.
Proc Natl Acad Sci U S A ; 117(49): 31448-31458, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33229571

RESUMO

Adult neural stem cells (NSC) serve as a reservoir for brain plasticity and origin for certain gliomas. Lineage tracing and genomic approaches have portrayed complex underlying heterogeneity within the major anatomical location for NSC, the subventricular zone (SVZ). To gain a comprehensive profile of NSC heterogeneity, we utilized a well-validated stem/progenitor-specific reporter transgene in concert with single-cell RNA sequencing to achieve unbiased analysis of SVZ cells from infancy to advanced age. The magnitude and high specificity of the resulting transcriptional datasets allow precise identification of the varied cell types embedded in the SVZ including specialized parenchymal cells (neurons, glia, microglia) and noncentral nervous system cells (endothelial, immune). Initial mining of the data delineates four quiescent NSC and three progenitor-cell subpopulations formed in a linear progression. Further evidence indicates that distinct stem and progenitor populations reside in different regions of the SVZ. As stem/progenitor populations progress from neonatal to advanced age, they acquire a deficiency in transition from quiescence to proliferation. Further data mining identifies stage-specific biological processes, transcription factor networks, and cell-surface markers for investigation of cellular identities, lineage relationships, and key regulatory pathways in adult NSC maintenance and neurogenesis.


Assuntos
Envelhecimento/genética , Linhagem da Célula , Ventrículos Laterais/anatomia & histologia , Ventrículos Laterais/citologia , Nicho de Células-Tronco/genética , Transcriptoma/genética , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem da Célula/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Transgenes
11.
Cancer Cell ; 38(3): 366-379.e8, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32649888

RESUMO

Glioblastoma, the predominant adult malignant brain tumor, has been computationally classified into molecular subtypes whose functional relevance remains to be comprehensively established. Tumors from genetically engineered glioblastoma mouse models initiated by identical driver mutations in distinct cells of origin portray unique transcriptional profiles reflective of their respective lineage. Here, we identify corresponding transcriptional profiles in human glioblastoma and describe patient-derived xenografts with species-conserved subtype-discriminating functional properties. The oligodendrocyte lineage-associated glioblastoma subtype requires functional ERBB3 and harbors unique therapeutic sensitivities. These results highlight the importance of cell lineage in glioblastoma independent of driver mutations and provide a methodology for functional glioblastoma classification for future clinical investigations.


Assuntos
Neoplasias Encefálicas/genética , Linhagem da Célula/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Dasatinibe/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , Camundongos Knockout , Camundongos Nus , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Nature ; 567(7748): 341-346, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30842654

RESUMO

Cancer-specific inhibitors that reflect the unique metabolic needs of cancer cells are rare. Here we describe Gboxin, a small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F0F1 ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxin in the mitochondrial matrix. Administration of a metabolically stable Gboxin analogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents.


Assuntos
Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Aloenxertos , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Linhagem Celular Tumoral , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/enzimologia , Membranas Mitocondriais/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Transplante de Neoplasias , Especificidade de Órgãos , Força Próton-Motriz/efeitos dos fármacos , ATPases Translocadoras de Prótons/antagonistas & inibidores , ATPases Translocadoras de Prótons/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Nat Neurosci ; 22(4): 545-555, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30778149

RESUMO

The contribution of lineage identity and differentiation state to malignant transformation is controversial. We have previously shown that adult neural stem and early progenitor cells give origin to glioblastoma. Here we systematically assessed the tumor-initiating potential of adult neural populations at various stages of lineage progression. Cell type-specific tamoxifen-inducible Cre recombinase transgenes were used to target glioblastoma-relevant tumor suppressors Nf1, Trp53 and Pten in late-stage neuronal progenitors, neuroblasts and differentiated neurons. Mutant mice showed cellular and molecular defects demonstrating the impact of tumor suppressor loss, with mutant neurons being the most resistant to early changes associated with tumor development. However, we observed no evidence of glioma formation. These studies show that increasing lineage restriction is accompanied by decreasing susceptibility to malignant transformation, indicating a glioblastoma cell-of-origin hierarchy in which stem cells sit at the apex and differentiated cell types are least susceptible to tumorigenesis.


Assuntos
Neoplasias Encefálicas/metabolismo , Linhagem da Célula , Glioblastoma/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proliferação de Células , Feminino , Masculino , Camundongos Transgênicos , Neurofibromina 1/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
Nat Commun ; 8(1): 1668, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29162814

RESUMO

Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Ketamina/farmacologia , Células-Tronco Neurais/metabolismo , Receptor trkB/metabolismo , Analgésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Hipocampo/citologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Receptor trkB/genética
15.
Cancer Cell ; 28(4): 429-440, 2015 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-26461091

RESUMO

A central question in glioblastoma multiforme (GBM) research is the identity of the tumor-initiating cell, and its contribution to the malignant phenotype and genomic state. We examine the potential of adult lineage-restricted progenitors to induce fully penetrant GBM using CNS progenitor-specific inducible Cre mice to mutate Nf1, Trp53, and Pten. We identify two phenotypically and molecularly distinct GBM subtypes governed by identical driver mutations. We demonstrate that the two subtypes arise from functionally independent pools of adult CNS progenitors. Despite histologic identity as GBM, these tumor types are separable based on the lineage of the tumor-initiating cell. These studies point to the cell of origin as a major determinant of GBM subtype diversity.


Assuntos
Células-Tronco Adultas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Sistema Nervoso Central/citologia , Glioblastoma/genética , Glioblastoma/patologia , Células-Tronco Adultas/metabolismo , Animais , Movimento Celular , Proliferação de Células , Humanos , Camundongos , Mutação , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neurofibromina 1/genética , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética
16.
J Neurosci ; 34(40): 13314-25, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25274811

RESUMO

Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Neurônios GABAérgicos/fisiologia , Hipocampo/citologia , Interneurônios/fisiologia , Neurogênese/fisiologia , Fatores Etários , Precursor de Proteína beta-Amiloide/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência , Nestina/genética , Nestina/metabolismo , Neurogênese/genética , Bloqueadores dos Canais de Sódio/farmacologia , Transmissão Sináptica/genética , Tetrodotoxina/farmacologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/deficiência
17.
Curr Alzheimer Res ; 9(2): 217-26, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21605029

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia in aging populations. Although amyloid plaques are the hallmark of AD, loss of synapses and synaptic dysfunction are closely associated with the duration and severity of cognitive impairment in AD patients. Amyloid precursor protein (APP) and its cleavage products including Aß have been suggested as homeostatic regulators of synaptic activity. APP manipulation and Aß application, in vitro and in vivo, affect synapse formation and synaptic transmission. Moreover, synaptic dysfunction and learning deficits precede Aß plaque deposition, suggesting that synaptic alterations may underlie the initial development of the disease. Because of the pivotal role of APP and Aß in AD pathogenesis, it is essential to understand how APP and Aß modulate synaptic function. Here, we review the roles that APP and Aß play at the synapses, with particular focus on recent findings for the importance of APP in synaptogenesis and synaptic function.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Sinapses/fisiologia , Animais , Humanos
18.
Cell Res ; 22(1): 78-89, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21769132

RESUMO

The amyloid precursor protein (APP) has been under intensive study in recent years, mainly due to its critical role in the pathogenesis of Alzheimer's disease (AD). ß-Amyloid (Aß) peptides generated from APP proteolytic cleavage can aggregate, leading to plaque formation in human AD brains. Point mutations of APP affecting Aß production are found to be causal for hereditary early onset familial AD. It is very likely that elucidating the physiological properties of APP will greatly facilitate the understanding of its role in AD pathogenesis. A number of APP loss- and gain-of-function models have been established in model organisms including Caenorhabditis elegans, Drosophila, zebrafish and mouse. These in vivo models provide us valuable insights into APP physiological functions. In addition, several knock-in mouse models expressing mutant APP at a physiological level are available to allow us to study AD pathogenesis without APP overexpression. This article will review the current physiological and pathophysiological animal models of APP.


Assuntos
Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/fisiologia , Placa Amiloide/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Drosophila/genética , Drosophila/metabolismo , Técnicas de Introdução de Genes , Humanos , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutação , Placa Amiloide/genética , Placa Amiloide/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
19.
PLoS One ; 6(3): e18006, 2011 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-21445342

RESUMO

BACKGROUND: Processing of Aß-precursor protein (APP) plays an important role in Alzheimer's Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr(668) is replaced by an Ala (T(668)A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T(668)A allele into the APLP2 knockout background showed that mutation of Thr(668) does not cause a defective phenotype. Notably, the T(668)A mutant APP is able to bind Mint1. CONCLUSIONS/SIGNIFICANCE: Our results argue against an important role of the Thr(668) residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved in those APP-mediated functions that prevent (NMJ) defects and early lethality in APLP2 null mice.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Peptidilprolil Isomerase/metabolismo , Treonina/metabolismo , Animais , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Peptidilprolil Isomerase de Interação com NIMA
20.
J Biol Chem ; 286(11): 8717-21, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21266574

RESUMO

The Aß-precursor protein (APP) intracellular domain is highly conserved and contains many potentially important residues, in particular the (682)YENPTY(687) motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Tyr(682) to Gly (Y682G). Crossing this allele to APP-like protein 2 (APLP2) knock-out background showed that mutation of Tyr(682) results in postnatal lethality and neuromuscular synapse defects similar to doubly deficient APP/APLP2 mice. Our results demonstrate that a single residue in the APP intracellular region, Tyr(682), is indispensable for the essential function of APP in developmental regulation.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Junção Neuromuscular/metabolismo , Tirosina/metabolismo , Alelos , Motivos de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Animais , Técnicas de Introdução de Genes , Camundongos , Camundongos Knockout , Junção Neuromuscular/genética , Estrutura Terciária de Proteína , Tirosina/genética
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