Impaired Amyloid Beta Clearance and Brain Microvascular Dysfunction are Present in the Tg-SwDI Mouse Model of Alzheimer’s Disease

May 26, 2020Neuroscience

Reduced Amyloid Beta Removal and Small Brain Blood Vessel Problems in a Mouse Model of Alzheimer's Disease

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Abstract

Isolated capillaries from Tg-SwDI mice contained increased levels of aggregated and oligomeric Aβ compared to wild type animals.

Decreased levels of P-glycoprotein (P-gp) were observed in Tg-SwDI mice, which is associated with impaired Aβ transport from the brain to the blood.
Increased levels of RAGE were found in Tg-SwDI mice, which is linked to enhanced Aβ transport from the blood to the brain.
A reduction in the tight junction protein occludin was noted in Tg-SwDI mice, correlating with increased blood-brain barrier (BBB) permeability.
Elevated Aβ aggregation may contribute to the observed neurovascular dysfunction in the Tg-SwDI mouse model of Alzheimer’s disease.

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Alzheimer's disease (AD) pathology is characterized by amyloid plaques containing amyloid beta (Aβ) peptides, neurofibrillary tangles containing hyperphosphorylated tau protein, and neuronal loss. In addition, Aβ deposition in brain microvessels, known as cerebral amyloid angiopathy (CAA), increases blood-brain barrier (BBB) permeability and induces vascular dysfunction which aggravates AD pathology. The aim of the present study was to characterize neurovascular dysfunction in the Tg-SwDI mouse model of AD. Isolated brain capillaries from wild type (WT) and Tg-SwDI mice were used to evaluate the expression of monomeric and aggregated forms of Aβ, P-glycoprotein (P-gp), the receptor for advance glycation end-products (RAGE) and the tight junction (TJs) proteins occludin and claudin-5. Cultured brain endothelial cells were used to analyze barrier function via fluorescein flux. Isolated capillaries from Tg-SwDI mice contained increased levels of aggregated and oligomeric Aβ compared to WT animals. Isolated capillaries from Tg-SwDI had decreased levels of P-gp, which transports Aβ from brain to blood, and increased levels of RAGE, which transports Aβ from blood to brain. In addition, the TJ protein occludin was decreased in Tg-SwDI mice relative to WT mice, which correlated with an increase in BBB permeability in cultured brain endothelial cells. These findings demonstrated that Tg-SwDI mice exhibit Aβ aggregation that is due, in part, to impaired Aβ clearance driven by both a decrease in P-gp and increase in RAGE protein levels in brain capillaries. Aβ aggregation promotes a decrease in the expression of the TJ protein occludin, and as consequence an increase in BBB permeability.

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Impaired Amyloid Beta Clearance and Brain Microvascular Dysfunction are Present in the Tg-SwDI Mouse Model of Alzheimer’s Disease

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