Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Key Points

  • The blood–brain barrier (BBB) protects neurons from factors present in the systemic circulation and maintains the highly regulated brain internal milieu, which is required for proper synaptic and neuronal functioning

  • BBB breakdown facilitates entry into the brain of neurotoxic blood-derived products, cells and pathogens and is associated with inflammatory and immune responses, which can initiate multiple neurodegenerative pathways

  • Neuroimaging studies have demonstrated early BBB dysfunction in Alzheimer disease and other neurodegenerative disorders, which is also supported by biofluid biomarker data and is consistently observed in post-mortem tissue

  • BBB dysfunction in neurodegenerative disorders includes increased BBB permeability, microbleeds, impaired glucose transport, impaired P-glycoprotein 1 function, perivascular deposits of blood-derived products, cellular infiltration and degeneration of pericytes and endothelial cells

Abstract

The blood–brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.

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Figure 1: The blood–brain barrier.
Figure 2: Key transport properties of the capillary endothelium.
Figure 3: Blood–brain barrier breakdown promotes neurodegeneration.
Figure 4: Blood–brain barrier dysfunction — implications for drug delivery.

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Acknowledgements

The work of B.V.Z. is supported by the National Institutes of Health grants R01AG023084, R01NS090904, R01NS034467, R01AG039452, R01NS100459 and 5P01AG052350 in addition to the Cure Alzheimer's Fund, Alzheimer's Association and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference number 16 CVD 05.

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All authors contributed to the literature search and to writing the manuscript. B.V.Z. worked closely with M.D.S. and A.P.S. to write the article and design the figures and tables.

Corresponding author

Correspondence to Berislav V. Zlokovic.

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The authors declare no competing financial interests.

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Glossary

Blood–brain barrier

(BBB). The continuous endothelial membrane of the brain vasculature, which has sealed cell-to-cell contacts and is sheathed by vascular mural cells and perivascular astrocyte end-feet; it functions to separate the circulating blood and brain compartments and strictly regulates blood-to-brain and brain-to-blood transport of solutes.

Pericytes

Mural cells that wrap the brain capillary endothelium and are important for formation and maintenance of the blood–brain barrier.

Neurodegeneration

Progressive neuronal dysfunction that causes neuronal degenerative changes and loss of neurons in various regions of the CNS in different neurodegenerative diseases.

Tight junctions

Endothelial proteins that tightly connect brain endothelial cells and provide the anatomical blood–brain barrier with its low paracellular permeability and high transendothelial electrical resistance.

Transmembrane diffusion

A type of passive transport across a cellular membrane in which the net movement of molecules occurs down their respective concentration gradients.

Carrier-mediated transport

(CMT). Transport of molecules across the blood–brain barrier down their concentration gradients via specific membrane carrier proteins.

Receptor-mediated transcytosis

(RMT). Transport of molecules across the blood–brain barrier in a highly specific fashion via membrane receptors that become internalized with the ligand during transendothelial transcytosis.

Cerebrospinal fluid

(CSF). A fluid continually produced in the choroid plexus that flows throughout the brain's ventricular system; it functions as a clearance pathway, maintains intraventricular intracranial pressure in the brain and is often analysed to measure levels of brain-derived biomarkers of disease.

Cerebral amyloid angiopathy

(CAA). In Alzheimer disease, amyloid deposition in the walls of small arteries and capillaries in the brain causes vascular degeneration and lobar microbleeds, which contribute to blood–brain barrier breakdown, infarcts, white matter changes and cognitive impairment.

Two-hit vascular hypothesis of AD

Blood vessel damage is thought to be the initial insult through which blood–brain barrier dysfunction and/or diminished brain perfusion lead directly to amyloid-β (Aβ)-independent secondary neuronal injury (first hit) and Aβ accumulation (second hit) in the brain owing to faulty Aβ clearance and increased antibody production.

E4 allele of apolipoprotein E

(APOE*ε4). This allele is the major genetic risk factor for sporadic late-onset Alzheimer disease.

Dynamic contrast-enhanced (DCE) MRI

A dynamic MRI sequence used to quantify regional blood–brain barrier permeability to a gadolinium contrast agent.

T2*-weighted and susceptibility-weighted imaging

(SWI). An MRI sequence in which haemosiderin deposits yield a hypointense signal, which enables regional in vivo measurement of cerebral microbleeds in the human brain.

18F-fluorodeoxyglucose

(FDG). An 18F-radiolabelled analogue of glucose that (unlike glucose) is not metabolized in the brain; FDG is used as a surrogate for glucose in PET studies to provide an estimate of glucose uptake by the brain across the blood–brain barrier via solute carrier family 2, facilitated glucose transporter member 1 (GLUT1).

LDL receptor-related protein 1

(LRP1). The major efflux transporter for amyloid-β (Aβ) at the blood–brain barrier; it is responsible for brain-to-blood Aβ clearance.

Verapamil

An 11C-radiolabelled PET ligand that enables the in vivo detection of P-glycoprotein 1 function at the blood–brain barrier in the living human brain.

Receptor for advanced glycosylation end products

(RAGE). The major influx transporter of amyloid-β (Aβ) at the blood–brain barrier; it contributes to Aβ accumulation in the brain, the inflammatory response, suppression of blood flow and blood–brain barrier breakdown.

RNA sequencing

A transcriptomic approach to reveal the presence and quantity of RNA transcripts in a biological sample.

Induced pluripotent stem cells

(iPSCs). Adult cells reprogrammed to induce an embryonic-like pluripotent state for the purposes of inducing differentiation into a cell type of interest for research studies and/or potential therapeutic efforts.

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Sweeney, M., Sagare, A. & Zlokovic, B. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14, 133–150 (2018). https://doi.org/10.1038/nrneurol.2017.188

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