Blood–brain barrier link to human cognitive impairment and Alzheimer’s disease

Barisano, Giuseppe; Montagne, Axel; Kisler, Kassandra; Schneider, Julie A.; Zloković, Berislav V.

doi:10.1038/s44161-021-00014-4

Cited by 66 publications

(59 citation statements)

References 103 publications

(182 reference statements)

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“…Indeed, a recent perspective linked blood-brain barrier breakdown to cognitive impairment in Alzheimer’s disease patients. 20 Overall, these publications indicate a critical role of a dysregulated blood-brain barrier in cognitive impairment and dementia.…”

Section: Aberrant Vegf Signaling In Alzheimer’s Diseasementioning

confidence: 99%

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

Ali

Bracko

2022

J Exp Neurosci

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Vascular dysfunction plays a critical role in the development of Alzheimer’s disease. Cerebral blood flow reductions of 10% to 25% present early in disease pathogenesis. Vascular Endothelial Growth Factor-A (VEGF-A) drives angiogenesis, which typically addresses blood flow reductions and global hypoxia. However, recent evidence suggests aberrant VEGF-A signaling in Alzheimer’s disease may undermine its physiological angiogenic function. Instead of improving cerebral blood flow, VEGF-A contributes to brain capillary stalls and blood flow reductions, likely accelerating cognitive decline. In this commentary, we explore the evidence for pathological VEGF signaling in Alzheimer’s disease, and discuss its implications for disease therapy.

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Section: Aberrant Vegf Signaling In Alzheimer’s Diseasementioning

confidence: 99%

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

Ali

Bracko

2022

J Exp Neurosci

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“…Unlike peripheral microvascular beds, which allow for diffusion of small molecules, the BBB is a highly restrictive barrier that is impermeable to most small molecules, with healthy barriers allowing access only to molecules with carriers or transporters. [28] Thus, we developed two assays to measure barrier permeability to small molecules in the m-µSiM, both of which were designed for measurements in the small volume (∼10 µL) of the ‘receiver’ channel of Component 2 (tissue-side) when dye is added to the donor well of Component 1 (blood-side). The first assay involves use of confocal microscopy to directly image the evolution of fluorescence in the trench of the membrane chip directly beneath the endothelial barrier after addition of a fluorescence tracer to Component 1’s well ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

The Modular µSiM: a Mass Produced, Rapidly Assembled, and Reconfigurable Platform for the Study of Barrier Tissue ModelsIn Vitro

McCloskey

Kasap

Ahmad

et al. 2022

Preprint

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Advanced in vitro tissue chip models can reduce and replace animal experimentation and may eventually support 'on-chip' clinical trials. To realize this potential, however, tissue chip platforms must be both mass-produced and reconfigurable to allow for customized design. To address these unmet needs, we introduce an extension of our μSiM (microdevice featuring a silicon-nitride membrane) platform. The modular μSiM (m-μSiM) uses mass-produced components to enable rapid assembly and reconfiguration by laboratories without knowledge of microfabrication. We demonstrate the utility of the m-μSiM by establishing an hiPSC-derived blood-brain barrier (BBB) in bioengineering and non-engineering, brain barriers focused laboratories. We develop and validate in situ and sampling-based assays of small molecule diffusion as a measure of barrier function. BBB properties show excellent interlaboratory agreement and match expectations from literature, validating the m-μSiM as a platform for barrier models and demonstrating successful dissemination of components and protocols. We then demonstrate the ability to quickly reconfigure the m-μSiM for co-culture and immune cell transmigration studies through addition of accessories and/or quick exchange of components. Because the development of modified components and accessories is easily achieved, custom designs of the m-μSiM should be accessible to any laboratory desiring a barrier-style tissue chip platform.

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“…The M1/M2 classification system is imperfect and there are several exceptions as has been shown in several studies on neurological disease states where substantial heterogeneity in microglial phenotypes have been demonstrated [ 179 , 180 ]. Indeed, microglial activation is strongly correlated with BBB dysfunction, which is an early event in neurological diseases, including ischemic stroke [ 96 ], Alzheimer’s disease [ 181 ], and epilepsy [ 182 ].…”

Section: Transport Mechanisms In Other Cell Types Of the Neurovascula...mentioning

confidence: 99%

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

Ronaldson

Davis

2022

Pharmaceutics

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Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have reported positive results for neuroprotective agents; however, only one compound (3K3A-activated protein C (3K3A-APC)) has advanced to Phase III clinical trial evaluation. One reason for these many failures is the lack of consideration of transport mechanisms at the blood–brain barrier (BBB) and neurovascular unit (NVU). These endogenous transport processes function as a “gateway” that is a primary determinant of efficacious brain concentrations for centrally acting drugs. Despite the knowledge that some neuroprotective agents (i.e., statins and memantine) are substrates for these endogenous BBB transporters, preclinical stroke studies have largely ignored the role of transporters in CNS drug disposition. Here, we review the current knowledge on specific BBB transporters that either limit drug uptake into the brain (i.e., ATP-binding cassette (ABC) transporters) or can be targeted for optimized drug delivery (i.e., solute carrier (SLC) transporters). Additionally, we highlight the current knowledge on transporter expression in astrocytes, microglia, pericytes, and neurons with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain.

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Blood–brain barrier link to human cognitive impairment and Alzheimer’s disease

Cited by 66 publications

References 103 publications

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

The Modular µSiM: a Mass Produced, Rapidly Assembled, and Reconfigurable Platform for the Study of Barrier Tissue ModelsIn Vitro

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

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