RESUMO
Alzheimer's disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aß and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis.
Assuntos
Doença de Alzheimer/genética , Hiperfagia/tratamento farmacológico , Resistência à Insulina/genética , Obesidade/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Animais , Glicemia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Alimentos/genética , Homeostase , Humanos , Hiperfagia/genética , Hiperfagia/patologia , Insulina/metabolismo , Insulina/uso terapêutico , Leptina/metabolismo , Leptina/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Camundongos , Camundongos Transgênicos , Obesidade/complicações , Obesidade/patologiaRESUMO
BACKGROUND: The accumulation of soluble oligomeric amyloid-ß peptide (oAß) proceeding the formation of senile plaques contributes to synaptic and memory deficits in Alzheimer's disease. Our previous studies have indentified scavenger receptor A (SR-A), especially SR-A type I (SR-AI), as prominent scavenger receptors on mediating oAß clearance by microglia while glycan moiety and scavenger receptor cysteine-rich (SRCR) domain may play the critical role. Macrophage receptor with collagenous structure (MARCO), another member of class A superfamily with a highly conserved SRCR domain, may also play the similar role on oAß internalization. However, the role of N-glycosylation and SRCR domain of SR-AI and MARCO on oAß internalization remains unclear. RESULT: We found that oAß internalization was diminished in the cells expressing SR-AI harboring mutations of dual N-glycosylation sites (i.e. N120Q-N143Q and N143Q-N184Q) while they were normally surface targeted. Normal oAß internalization was observed in 10 SR-AI-SRCR and 4 MARCO-SRCR surface targeted mutants. Alternatively, the SRCR mutants at ß-sheet and α-helix and on disulfide bone formation obstructed receptor's N-glycosylation and surface targeting. CONCLUSION: Our study reveals that N-glycan moiety is more critical than SRCR domain for SR-A-mediated oAß internalization.
Assuntos
Proteínas de Transporte/metabolismo , Receptores Imunológicos/metabolismo , Substituição de Aminoácidos , Peptídeos beta-Amiloides , Animais , Células COS , Proteínas de Transporte/genética , Chlorocebus aethiops , Glicosilação , Células HEK293 , Humanos , Mutação de Sentido Incorreto , Estrutura Terciária de Proteína , Transporte Proteico/genética , Receptores Imunológicos/genética , Fatores de Processamento de Serina-ArgininaRESUMO
The cerebral cortex is compartmentalized into multiple regions, including the newly evolved neocortex and evolutionarily older paleocortex and archicortex. These broad cortical regions can be further subdivided into different functional domains, each with its own unique cytoarchitecture and distinct set of input and output projections to perform specific functions. While many excitatory projection neurons show region-specific gene expression profiles, the cells are derived from the seemingly uniform progenitors in the dorsal telencephalon. Much progress has been made in defining the genetic mechanisms involved in generating the morphological and functional diversity of the central nervous system. In this review, we summarize the current knowledge of mouse corticogenesis and discuss key events involved in cortical patterning during early developmental stages.
Assuntos
Córtex Cerebral , Neocórtex , Camundongos , Animais , Regulação da Expressão Gênica no Desenvolvimento/genéticaRESUMO
Diabetes is a risk factor for Alzheimer's disease (AD), a chronic neurodegenerative disease. We and others have shown prediabetes, including hyperglycemia and obesity induced by high fat and high sucrose diets, is associated with exacerbated amyloid beta (Aß) accumulation and cognitive impairment in AD transgenic mice. However, whether hyperglycemia reduce glial clearance of oligomeric amyloid-ß (oAß), the most neurotoxic Aß aggregate, remains unclear. Mixed glial cultures simulating the coexistence of astrocytes and microglia in the neural microenvironment were established to investigate glial clearance of oAß under normoglycemia and chronic hyperglycemia. Ramified microglia and low IL-1ß release were observed in mixed glia cultures. In contrast, amoeboid-like microglia and higher IL-1ß release were observed in primary microglia cultures. APPswe/PS1dE9 transgenic mice are a commonly used AD mouse model. Microglia close to senile plaques in APPswe/PS1dE9 transgenic mice exposed to normoglycemia or chronic hyperglycemia exhibited an amoeboid-like morphology; other microglia were ramified. Therefore, mixed glia cultures reproduce the in vivo ramified microglial morphology. To investigate the impact of sustained high-glucose conditions on glial oAß clearance, mixed glia were cultured in media containing 5.5 mM glucose (normal glucose, NG) or 25 mM glucose (high glucose, HG) for 16 days. Compared to NG, HG reduced the steady-state level of oAß puncta internalized by microglia and astrocytes and decreased oAß degradation kinetics. Furthermore, the lysosomal acidification and lysosomal hydrolysis activity of microglia and astrocytes were lower in HG with and without oAß treatment than NG. Moreover, HG reduced mitochondrial membrane potential and ATP levels in mixed glia, which can lead to reduced lysosomal function. Overall, continuous high glucose reduces microglial and astrocytic ATP production and lysosome activity which may lead to decreased glial oAß degradation. Our study reveals diabetes-induced hyperglycemia hinders glial oAß clearance and contributes to oAß accumulation in AD pathogenesis.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Glucose/efeitos adversos , Hiperglicemia/metabolismo , Lisossomos/metabolismo , Neuroglia/citologia , Doença de Alzheimer/genética , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hiperglicemia/genética , Interleucina-1beta/metabolismo , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Proteólise , RatosRESUMO
Background: The differential diagnosis of estrogen receptor-positive (ER+) pathway-activated systems by using a labeled antiestrogen helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. The authors' purpose was to synthesize chelator-tamoxifen conjugates for imaging ER (+) diseases. Materials and Methods: A hydroxypropyl linker was incorporated between either cyclam or cyclam diacetic acid and tamoxifen analog to produce SC-05-L-1 (Z-1-(1,4,8,11-tetraazacyclotetradecan-1-yl)-3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)propan-2-ol) and SC-05-N-1 (Z-2,2'-(4-(3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)-2-hydroxy-propyl)-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid), respectively. In vitro cell uptake and cell/media ratios of 99mTc-SC-05-L-1 and 99mTc- SC-05-N-1 in ER (+) ovarian cancer cells (TOV-112D and OVCAR3) were performed. To ascertain the specificity of cell uptake, the cell uptake was blocked with estrone. In vivo 99mTc-SC-05-L-1 or 99mTc-SC-05-N-1 single-photon emission computed tomography/computed tomography was conducted in tumor-bearing rodents and compared to 18F-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/magnetic resonance imaging (a reference technology). Results: The radiochemical purities of 99mTc-SC-05-L-1 and 99mTc-SC-05-N-1 were greater than 99% (n = 10). 99mTc-SC-05-L-1 had higher cell/media ratios than 99mTc-SC-05-N-1 in OVCAR-3 ER (+) cells. The cell uptake of 99mTc-SC-05-L-1 was blocked 80% by estrone indicating an ER-mediated process occurred. 99mTc-SC-05-N-1 was further selected for in vivo imaging studies due to higher maximum tolerated dose and superior water solubility than 99mTc-SC-05-L-1. 99mTc-SC-05-N-1 showed higher tumor uptake and tumor/muscle count density ratios than 18F-FDG in tumor-bearing rodents. Conclusion: 99mTc-SC-05-N-1 showed better differential diagnosis of ovarian tumors than 18F-FDG, indicating great promising in chelator-tamoxifen conjugate for ER pathway-directed systems imaging.
Assuntos
Neoplasias Ovarianas , Receptores de Estrogênio , Apoptose , Linhagem Celular Tumoral , Quelantes , Feminino , Humanos , Compostos de Organotecnécio , Tamoxifeno/farmacologiaRESUMO
High-fat and high-sugar diets contribute to the prevalence of type 2 diabetes and Alzheimer's disease (AD). Although the impact of high-fat diets on AD pathogenesis has been established, the effect of high-sucrose diets (HSDs) on AD pathogenesis remains unclear. This study sought to determine the impact of HSDs on AD-related pathologies. Male APPswe/PS1dE9 (APP/PS1) transgenic and wild-type mice were provided with HSD and their cognitive and hypothalamus-related noncognitive parameters, including feeding behaviors and glycemic regulation, were compared. HSD-fed APP/PS1 mice showed increased neuroinflammation, as well as increased cortical and serum levels of amyloid-ß. HSD-fed APP/PS1 mice showed aggravated obesity, hyperinsulinemia, insulin resistance, and leptin resistance, but there was no induction of hyperphagia or hyperleptinemia. Leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the dorsomedial and ventromedial hypothalamus was reduced in HSD-fed APP/PS1 mice, which might be associated with attenuated food-anticipatory activity, glycemic dysregulation, and AD-related noncognitive symptoms. Our study demonstrates that HSD aggravates metabolic stresses, increases AD-related pathologies, and attenuates hypothalamic leptin signaling in APP/PS1 mice.