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Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes.

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Date

2022-09-26

Authors

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
Simo, Rafael
Bacskai, Brian J

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BioMed Central
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Abstract

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.

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Animals
Mice
Alzheimer disease
Disease models, animal
Diabetes mellitus, type 2
Prediabetic state
Cerebral amyloid angiopathy
Amyloid beta-peptides
Plaque, amyloid
Brain
Matrix metalloproteinases

DeCS Terms

Angiopatía amiloide cerebral
Diabetes mellitus tipo 2
Encéfalo
Enfermedad de Alzheimer
Estado prediabético
Metaloproteinasas de la matriz
Placa amiloide
Péptidos beta-amiloides

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Keywords

Alzheimer’s disease, Amyloid, Matrix metalloproteinases, Multiphoton microscopy, Oxidative stress, Prediabetes, Type 2 diabetes

Citation

Vargas-Soria M, Ramos-Rodriguez JJ, Del Marco A, Hierro-Bujalance C, Carranza-Naval MJ, Calvo-Rodriguez M, et al. Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes. Fluids Barriers CNS. 2022 Nov 7;19(1):88