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Review
. 2023 Mar;54(3):661-672.
doi: 10.1161/STROKEAHA.122.040578. Epub 2023 Feb 27.

Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments

Anuska V Andjelkovic  1   2 , Muyu Situ  3 , Ali Francisco Citalan-Madrid  1 , Svetlana M Stamatovic  1 , Jianming Xiang  2 , Richard F Keep  2   4
Affiliations
Review

Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments

Anuska V Andjelkovic et al. Stroke. 2023 Mar.

Abstract

Cerebral endothelial cells and their linking tight junctions form a unique, dynamic and multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular cells and components forming the neurovascular unit. This review examines BBB and neurovascular unit changes in normal aging and in neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy and vascular dementia. Increasing evidence indicates BBB dysfunction contributes to neurodegeneration. Mechanisms underlying BBB dysfunction are outlined (endothelium and neurovascular unit mediated) as is the BBB as a therapeutic target including increasing the uptake of systemically delivered therapeutics across the BBB, enhancing clearance of potential neurotoxic compounds via the BBB, and preventing BBB dysfunction. Finally, a need for novel biomarkers of BBB dysfunction is addressed.

Keywords: aging; blood-brain barrier; cerebral amyloid angiopathy; neurodegeneration; neurovascular unit; vascular dementia.

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Figures

Figure 1:
Figure 1:
Blood brain barrier (BBB) and neurovascular unit (NVU). Schematic representation of cellular structure of BBB/NVU. BBB-endowed brain endothelial cells are characterized by junctional complex (box) that restricts paracellular movement. The junctional complex is composed from tight junctions, adherens junctions and gap junctions. ECM- extracellular matrix. Created with BioRender.com.
Figure 2.
Figure 2.
BBB and NVU in aging, AD and associated vasculopathy (CAA) and in vascular dementia. Schematic representation of BBB/NVU remodeling in aging and types of neurodegeneration. ECM-extracellular matrix, BM basement membrane. Created with BioRender.com.
Figure 3.
Figure 3.
Representative images of MRI analyses of BBB permeability in CAA murine model (Tg-SwDi) and control mice. BBB hyperpermeability to Gd-DTPA and analyzed by T1w MRI and T1 map of BBB transfer coefficient Ki varying from 0–1min−1. Histologically, BBB permeability was confirmed by visualizing BBB leakiness to cadaverine-594 (Red). Blood vessels (green, Tomato lectin-DyLight 488) with Aβ deposits (blue, Amyloid Glo, arrowhead) showed increased leakiness to cadaverine (arrow) vs. control mice. Increased BBB permeability was associated with reduced claudin-5 (green) and ZO-1 (purple) interaction (yellow arrowhead) and expression. Representative images are the maximum 3D projection of z-stack (400μm). Scale bar 100μm.
Figure 4.
Figure 4.
Aging and CAA remodeling of the BBB/NVU. Representative image 3D projection of z-stack (400mm) with immunofluorescence for cortical blood vessels (red-Tomato lectin DyLight-596, or green Tomato lectin DyLight-488), astrocytes (GFAP, Far Red), microglia (Iba1, green), pericytes (PDGFRβ- FarRed) and Aβ with Amyloid Glo (blue) in young (6 months) and old (18 months) control mice and mice with CAA, Tg-SwDI (16 months). Arrowhead indicates Aβ deposition. Scale bar=100μm.
See this image and copyright information in PMC

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