1. Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer's mouse model
- Author
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Laura D. Weinstock, Sitara B. Sankar, Monica Garcia-Alloza, Levi B. Wood, Carmen Hierro-Bujalance, Juan Jose Ramos-Rodriguez, Carmen Infante-Garcia, Cecilia Fernández-Ponce, [Sankar,SB, Weinstock,LD, Wood,LB] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. [Infante-Garcia,C, Ramos-Rodriguez,JJ, Hierro-Bujalance,C, Garcia-Alloza,M] Division of Physiology, School of Medicine, Universidad de Cadiz, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Cadiz, Spain. [Infante-Garcia,C, Fernandez-Ponce,C, Garcia-Alloza,M] Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain. [Ramos-Rodriguez,JJ] Departamento de Fisiología, Facultad de Ciencias de la Salud, Universidad de Granada, Granada, Spain. [Fernandez-Ponce,C] Área de Inmunología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain. [Wood,LB] George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, USA., This work was funded in part by Programa Estatal de I+D+I orientada a los Retos de la Sociedad (BFU 2016-75038-R), financed by the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Ciencia, Innovación y Universidades, Explora Ciencia, Ministerio de Ciencia, Innovación y Universidades (BFU2017-91910-EXP), Subvención para la financiación de la investigación y la innovación biomédica y en ciencias de la salud en el marco de la Iniciativa Territorial Integrada 2014–2020 para la provincia de Cádiz, Consejeria de Salud, Junta de Andalucia, Union Europea, financed by the Fondo de Desarrollo Regional (FEDER) (PI-0008-2017) (M.G.A.). This work was also supported by startup funds from the George W. Woodruff School of Mechanical Engineering at Georgia Tech (L.B.W.) and by the National Institutes of Health under grant number R33 ES025661 04S1. LDW was supported in part by the National Institutes of Health Cell and Tissue Engineering Biotechnology Training Grant (T32-GM008433). Authors declare no conflict of interest., and Biomedicina, Biotecnología y Salud Pública
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Blood Glucose ,Pathology ,medicine.medical_treatment ,Type 2 diabetes ,Type 1 diabetes (T1D) ,lcsh:RC346-429 ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Mice ,0302 clinical medicine ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Insulin ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic [Medical Subject Headings] ,Type 2 diabetes (T2D) ,Cerebral Cortex ,0303 health sciences ,biology ,General Neuroscience ,Citocinas ,Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Experimental [Medical Subject Headings] ,3. Good health ,Cytokine profile ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Peptide Hormones::Pancreatic Hormones::Insulins [Medical Subject Headings] ,Cytokine ,Diabetes mellitus tipo 2 ,Neurology ,Diabetes mellitus tipo 1 ,Cytokines ,Microglia ,Pre-diabetes ,medicine.medical_specialty ,Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings] ,Amyloid beta ,Immunology ,Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral Cortex [Medical Subject Headings] ,Mice, Transgenic ,Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings] ,Diet, High-Fat ,Anatomy::Nervous System::Neuroglia::Microglia [Medical Subject Headings] ,Streptozocin ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Diet, High-Fat [Medical Subject Headings] ,Downregulation and upregulation ,Alzheimer Disease ,Diabetes mellitus ,medicine ,Animals ,Humans ,Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 1 [Medical Subject Headings] ,lcsh:Neurology. Diseases of the nervous system ,Neuroinflammation ,030304 developmental biology ,Type 1 diabetes ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Amyloid beta-Peptides ,business.industry ,Research ,Estado prediabético ,Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings] ,Chemicals and Drugs::Carbohydrates::Glycosides::Aminoglycosides::Streptozocin [Medical Subject Headings] ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-Peptides [Medical Subject Headings] ,medicine.disease ,Diabetes Mellitus, Type 1 ,Diabetes Mellitus, Type 2 ,biology.protein ,business ,030217 neurology & neurosurgery ,Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose::Blood Glucose [Medical Subject Headings] - Abstract
Background: Diabetes is a risk factor for developing Alzheimer’s disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aβ pathology and increased expression of glial activation markers in APPswe/ PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. Results: Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1β, and MCP-1) and proinflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aβ1-40, Aβ1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. Conclusions: Altogether, our multiplexed analysis of cytokines shows that Alzheimer’s and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aβ and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD., This work was funded in part by Programa Estatal de I+D+I orientada a los Retos de la Sociedad (BFU 2016-75038-R), financed by the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Ciencia, Innovación y Universidades, Explora Ciencia, Ministerio de Ciencia, Innovación y Universidades (BFU2017-91910-EXP), Subvención para la financiación de la investigación y la innovación biomédica y en ciencias de la salud en el marco de la Iniciativa Territorial Integrada 2014–2020 para la provincia de Cádiz, Consejeria de Salud, Junta de Andalucia, Union Europea, financed by the Fondo de Desarrollo Regional (FEDER) (PI-0008- 2017) (M.G.A.). This work was also supported by startup funds from the George W. Woodruff School of Mechanical Engineering at Georgia Tech (L.B.W.) and by the National Institutes of Health under grant number R33 ES025661 04S1. LDW was supported in part by the National Institutes of Health Cell and Tissue Engineering Biotechnology Training Grant (T32- GM008433).
- Published
- 2020