1. Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes
- Author
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Vargas-Soria, Maria, Ramos-Rodriguez, Juan Jose, del Marco, Angel, Hierro-Bujalance, Carmen, Carranza-Naval, Maria Jose, Calvo-Rodriguez, Maria, van Veluw, Susanne J., Stitt, Alan W., Simó Canonge, Rafael, Bacskai, Brian J., Infante-Garcia, Carmen, Garcia-Alloza, Monica, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Vargas-Soria M, del Marco A, Hierro-Bujalance C] Division of Physiology, School of Medicine, University of Cadiz, Cadiz, Spain. Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. [Ramos-Rodriguez JJ] Division of Physiology, School of Medicine, University of Cadiz, Cadiz, Spain. Currently at Department of Physiology, School of Health Sciences, University of Granada, Granada, Spain. [Carranza-Naval MJ] Division of Physiology. School of Medicine, University of Cadiz, Cadiz, Spain. Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. Salus Infirmorum, University of Cadiz, Cadiz, Spain. [Calvo-Rodriguez M] Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA. [Simó R] Grup de Recerca en Diabetis i Metabolisme, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Amyloid beta-Peptides - metabolism ,Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Dementia::Alzheimer Disease [DISEASES] ,enfermedades nutricionales y metabólicas::enfermedades metabólicas::trastornos del metabolismo de la glucosa::diabetes mellitus::diabetes mellitus tipo II [ENFERMEDADES] ,Amyloid ,Alzheimer´s disease ,Cerebral Amyloid Angiopathy - metabolism ,enfermedades nutricionales y metabólicas::enfermedades metabólicas::deficiencias de la proteostasis::amiloidosis::angiopatía amiloide cerebral [ENFERMEDADES] ,Plaque, Amyloid ,Diabetes Mellitus, Type 2 - complications - metabolism - pathology ,Diabetis no-insulinodependent ,Multiphoton microscopy ,Prediabetic State ,Cellular and Molecular Neuroscience ,Mice ,SDG 3 - Good Health and Well-being ,Developmental Neuroscience ,Alzheimer Disease ,Plaque, Amyloid - complications - metabolism - pathology ,Animals ,Prediabetic State - complications - metabolism - pathology ,Alzheimer Disease - metabolism ,Ratolins ,Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Mice [ORGANISMS] ,Brain - metabolism ,Amyloid beta-Peptides ,Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [DISEASES] ,Brain ,Type 2 diabetes ,General Medicine ,Alzheimer's disease ,Matrix Metalloproteinases ,Alzheimer, Malaltia d' ,Disease Models, Animal ,Cerebral Amyloid Angiopathy ,Matrix metalloproteinases ,Neurology ,enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::demencia::enfermedad de Alzheimer [ENFERMEDADES] ,Diabetes Mellitus, Type 2 ,Oxidative stress ,Nutritional and Metabolic Diseases::Metabolic Diseases::Proteostasis Deficiencies::Amyloidosis::Cerebral Amyloid Angiopathy [DISEASES] ,Amiloïdosi ,Alzheimer’s disease ,Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratones [ORGANISMOS] ,Prediabetes - Abstract
Background: While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods: To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/ PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ ™ Gelatin, and vascular functionality. Results: We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions: Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature., University of Cadiz Predoctoral Fellowship, European Commission, European Commission Joint Research Centre GA 847749, Programa Estatal de Generacion de Conocimiento y Fortalecimiento Cientifico y Tecnologico del Sistema de I + D + i y del Programa Estatal de I + D +i Orientada a los Retos de la Sociedad, del Plan Estatal de Investigacion Cientifica y Tecnica y de Innovaci PID2020-115499RB-I00/AEI, Agencia Estatal de Investigacion (AEI) BFU 2016-75038-R, Spanish Government Spanish Government, Andalucia se mueve con Europa P20-00928
- Published
- 2022