Circulating Exosomes from Alzheimer’s Disease Suppress Vascular Endothelial-Cadherin Expression and Induce Barrier Dysfunction in Recipient Brain Microvascular Endothelial Cell

Article type: Research Article

Authors: Bei, Jiani^a | Miranda-Morales, Ernesto G.^b | Gan, Qini^c | Qiu, Yuan^a | Husseinzadeh, Sorosh^a | Liew, Jia Yi^d | Chang, Qing^a | Krishnan, Balaji^b | Gaitas, Angelo^e | Yuan, Subo^d | Felicella, Michelle^a | Qiu, Wei Qiao^{c; *} | Fang, Xiang^{b; *} | Gong, Bin^{a; *}

Affiliations: [a] Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA | [b] Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA | [c] Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, USA | [d] Department of Neurobiology, University of Texas Medical Branch, Galveston, TX, USA | [e] The Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Correspondence: [*] Correspondence to: Bin Gong, MD, PhD, Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. Tel.: +1 409 266 6682; Fax: +1 409 266 6810; E-mail: [email protected]. and Xiang Fang, MD, PhD, Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA. Tel.: +1 409 772 8053; Fax: +1 409 772 6904; E-mail: [email protected]. and Wei Qiao Qiu, MD, PhD, Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA 02118, USA. Tel.: +1 617 358 1886; E-mail: [email protected].

Abstract: Background:Blood-brain barrier (BBB) breakdown is a crucial aspect of Alzheimer’s disease (AD) progression. Dysfunction in BBB is primarily caused by impaired tight junction and adherens junction proteins in brain microvascular endothelial cells (BMECs). The role of adherens junctions in AD-related BBB dysfunction remains unclear. Exosomes from senescent cells have unique characteristics and contribute to modulating the phenotype of recipient cells. However, it remains unknown if and how these exosomes cause BMEC dysfunction in AD. Objective:This study aimed to investigate the impact of AD circulating exosomes on brain endothelial dysfunction. Methods:Exosomes were isolated from sera of AD patients and age- and sex-matched cognitively normal controls using size-exclusion chromatography. The study measured the biomechanical nature of BMECs’ endothelial barrier, the lateral binding forces between live BMECs. Paracellular expressions of the key adherens junction protein vascular endothelial (VE)-cadherin were visualized in BMEC cultures and a 3D BBB model using human BMECs and pericytes. VE-cadherin signals were also examined in brain tissues from AD patients and normal controls. Results:Circulating exosomes from AD patients reduced VE-cadherin expression levels and impaired barrier function in recipient BMECs. Immunostaining analysis demonstrated that AD exosomes damaged VE-cadherin integrity in a 3D microvascular tubule formation model. The study found that AD exosomes weakened BBB integrity depending on their RNA content. Additionally, diminished microvascular VE-cadherin expression was observed in AD brains compared to controls. Conclusion:These findings highlight the significant role of circulating exosomes from AD patients in damaging adherens junctions of recipient BMECs, dependent on exosomal RNA.

Keywords: Alzheimer’s disease, blood-brain barrier, 3D microvascular model, exosome, endothelial barrier dysfunction, fluidic AFM, VE-cadherin

DOI: 10.3233/JAD-230347

Journal: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 869-885, 2023