Journal Article

Endothelial Dysfunctions in Blood–Brain Barrier Breakdown in Alzheimer's Disease: From Mechanisms to Potential Therapies

Zhang, Zaijun, Hoi, Maggie Pui Man, Yue, Qian, Xie, Ningqing, Yang, Deguang, Leng, Xinyue

2024

Overview

Recent research has shown the presence of blood–brain barrier (BBB) breakdown in Alzheimer's disease (AD). BBB is a dynamic interface consisting of a continuous monolayer of brain endothelial cells (BECs) enveloped by pericytes and astrocytes. The restricted permeability of BBB strictly controls the exchange of substances between blood and brain parenchyma, which is crucial for brain homeostasis by excluding blood‐derived detrimental factors and pumping out brain‐derived toxic molecules. BBB breakdown in AD is featured as a series of BEC pathologies such as increased paracellular permeability, abnormal levels and functions of transporters, and inflammatory or oxidative profile, which may disturb the substance transportation across BBB, thereafter induce CNS disorders such as hypometabolism, Aβ accumulation, and neuroinflammation, eventually aggravate cognitive decline. Therefore, it seems important to protect BEC properties for BBB maintenance and neuroprotection. In this review, we thoroughly summarized the pathological alterations of BEC properties reported in AD patients and numerous AD models, including paracellular permeability, influx and efflux transporters, and inflammatory and oxidative profiles, and probably associated underlying mechanisms. Then we reviewed current therapeutic agents that are effective in ameliorating a series of BEC pathologies, and ultimately protecting BBB integrity and cognitive functions. Regarding the current drug development for AD proceeds extremely hard, this review aims to discuss the therapeutic potentials of targeting BEC pathologies and BBB maintenance for AD treatment, therefore expecting to shed a light on the future AD drug development by targeting BEC pathologies and BBB protection. Blood–brain barrier (BBB) works as a crucial structure separating central nervous system (CNS) and circulating system. The highly organized endothelial junctions and transporters strictly restricts substance exchange across BBB to maintain the homeostasis of CNS. In Alzheimer's disease, BBB breakdown has been widely detected, featured as a series of brain endothelial cell (BEC) pathologies, including increased permeability, abnormal levels and functions of influx and efflux transporters, as well as inflammatory and oxidative profile. The goal for BEC‐targeting treatment in AD is to maintain the integrity of BBB and accelerate the clearance of brain‐derived Aβ species through BBB. BEC‐targeting treatment for AD mainly focuses on regulating a series of pathological processes including inflammation, oxidative stress, autophagy, apoptosis, and several signaling such as angiogenic and Wnt/β‐catenin pathway, as well as modulating Aβ clearance pathway and so on. Targeting various BEC pathologies have shown therapeutic potentials in protecting BBB and improving cognitive functions in AD.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Aging / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Animals / Astrocytes / BBB protection / Biomarkers / Blood-brain barrier / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - pathology / Cognitive ability / Dementia / Disease / Drug development / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Homeostasis / Humans / influx and efflux transporter / Magnetic resonance imaging / Membrane permeability / Mutation / Neurodegenerative diseases / Neuroprotection / Neurotoxicity / paracellular permeability / Parenchyma / Pericytes / Permeability / Proteins / Review / Toxicity / vascular inflammation / β-Amyloid