Abstract
Transgenic mouse models of Alzheimer’s disease (AD) overexpress mutations of the human amyloid protein precursor (APP) and presenilin-1 (PSEN1) genes, which are known causes of amyloid pathology in familial AD. However, animal models for studying AD in the context of aging and age-related co-morbidities, such as blood–brain barrier (BBB) disruptions, are lacking. More recently, aged and progeroid mouse models have been proposed as alternatives to study aging-related AD, but the toxicity of murine amyloid-beta protein (Aβ) is not well defined. In this study, we aimed to study the potential toxicity of murine Aβ on brain endothelial cells and astrocytes, which are important components of the BBB, using mouse brain endothelial cells (bEnd.3) and astrocytes (C8-D1A). Murine-soluble Aβ (1–42) oligomers (sAβO42) (10 µM) induced negligible injuries in an endothelial monolayer but induced significant barrier disruptions in a bEnd.3 and C8-D1A co-culture. Similar results of endothelial perturbation were observed in a bEnd.3 monolayer treated with astrocyte-conditioned medium (ACM) generated by astrocytes exposed to sAβO42 (ACM-sAβO42), while additional exogenous sAβO42 did not cause further damage. Western blot analysis showed that ACM-sAβO42 altered the basal activities of vascular endothelial growth factor receptor 2 (VEGFR2), eNOS, and the signaling of the MEK/ERK and Akt pathways in bEnd.3. Our results showed that murine sAβO42 was moderately toxic to an endothelial and astrocyte co-culture. These damaging effects on the endothelial barrier were induced by deleterious soluble factors released from astrocytes, which disrupted endothelial VEGFR2 signaling and perturbed cell survival and barrier stabilization.
Highlights
The blood–brain barrier (BBB) consists of a tightly sealed monolayer of brain endothelial cells together with other supporting cells in the neurovascular units, including pericytes, astrocytes, and neurons [1]
The majority of soluble Aβ species obtained from the brains of Alzheimer’s disease (AD) patients were oligomers of high molecular weight (HMW) (>70 kDa), while Aβ42 has been shown to induce higher cytotoxicity than Aβ40 [22]
We further investigated the contribution of astrocytes in our model by using a bEnd.3 + C8-D1A coculture and astrocyte-conditioned medium (ACM) derived from C8-D1A
Summary
The blood–brain barrier (BBB) consists of a tightly sealed monolayer of brain endothelial cells together with other supporting cells in the neurovascular units, including pericytes, astrocytes, and neurons [1]. Brain endothelial cells are connected by tight junctions (TJ) and adherens junctions (AJ) and the expressions of their junctional proteins (e.g., zonula occludens-1 (ZO-1), claudin-5, occludin, junction adhesion molecules (JAMs), vascular endothelial cadherin (VE-cadherin), platelet endothelial cell adhesion molecule 1 (PECAM-1) and β-catenin) are directly related to the integrity of the BBB [2]. This physiological barrier is a gatekeeper for brain homeostasis, limiting the entry of potentially harmful blood-derived agents, such as plasma-derived components and immune cells, into the central nervous system (CNS), as well as clearing metabolic waste products and potential neurotoxic molecules from parenchyma to the blood. The alteration in BBB functions likely precedes the progressive and irreversible cognitive decline in AD
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