Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer's disease and type two diabetes
Vargas-Soria, Maria (Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Ramos-Rodriguez, Juan Jose (Universidad de Granada)
Del Marco, Angel (Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Hierro-Bujalance, Carmen (Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Carranza-Naval, Maria Jose (Universidad de Cádiz)
Calvo-Rodriguez, Maria (Harvard Medical School)
van Veluw, Susanne J. (Harvard Medical School)
Stitt, Alan W. (Queen's University Belfast)
Simó Canonge, Rafael (Hospital Universitari Vall d'Hebron)
Bacskai, Brian J. (Harvard Medical School)
Infante-Garcia, Carmen (Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Garcia-Alloza, Monica (Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Universitat Autònoma de Barcelona

Fecha:	2022
Resumen:	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. 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. 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. 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.
Ayudas:	European Commission 847749 Agencia Estatal de Investigación PID2020-115499RB-I00 Agencia Estatal de Investigación BFU2016-75038-R
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Alzheimer's disease ; Type 2 diabetes ; Prediabetes ; Multiphoton microscopy ; Amyloid ; Oxidative stress ; Matrix metalloproteinases
Publicado en:	Fluids and Barriers of the CNS, Vol. 19 (november 2022) , ISSN 2045-8118

DOI: 10.1186/s12987-022-00380-6
PMID: 36345028

13 p, 3.6 MB

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