@misc{10481/78314,
year = {2022},
month = {11},
url = {https://hdl.handle.net/10481/78314},
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.},
organization = {University of Cadiz Predoctoral Fellowship},
organization = {European Commission},
organization = {European Commission Joint Research Centre	GA 847749},
organization = {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},
organization = {Agencia Estatal de Investigacion (AEI)	BFU 2016-75038-R},
organization = {European Commission},
organization = {Spanish Government		
Spanish Government},
organization = {Andalucia se mueve con Europa	P20-00928},
publisher = {BMC},
keywords = {Alzheimer´s disease},
keywords = {Type 2 diabetes},
keywords = {Prediabetes},
keywords = {Multiphoton microscopy},
keywords = {Amyloid},
keywords = {Oxidative stress},
keywords = {Matrix metalloproteinases},
title = {Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes},
doi = {10.1186/s12987-022-00380-6},
author = {Vargas Soria, María and Ramos Rodríguez, Juan José},
}