Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

Wang, Dong; Chen, Fanglian; Han, Zhaoli; Yin, Zhenyu; Ge, Xintong; Lei, Ping

doi:10.3389/fncel.2021.695479

Cited by 98 publications

(68 citation statements)

References 170 publications

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“…Another important point is that BBB is vital to regulate the brain Aβ metabolism and load, and Aβ deposition could result from an inefficient clearance through BBB [132,134]. Firstly, Shibata et al [135] and other authors pointed out that brain Aβ is mainly cleared across BBB via LRP-1.…”

Section: Bbb As a Target Of Systemic Inflammation: Importance To Alzheimer's Disease Developmentmentioning

confidence: 99%

“…Importantly, the LRP-1 content is down-regulated in AD brain [132,[135][136][137]. After that, the function of other transporters in the Aβ clearance and AD pathogenesis have been studied, such as RAGE [132,134,138]. On the other hand, Aβ deposition appears to cause BBB damage but is not well evidenced [134].…”

Section: Bbb As a Target Of Systemic Inflammation: Importance To Alzheimer's Disease Developmentmentioning

confidence: 99%

“…After that, the function of other transporters in the Aβ clearance and AD pathogenesis have been studied, such as RAGE [132,134,138]. On the other hand, Aβ deposition appears to cause BBB damage but is not well evidenced [134]. In addition, it has been demonstrated that BBB endothelial cells respond to truncated tau fragments, ultimately resulting in BBB disruption [139,140] In parallel, other research groups demonstrated the presence and accumulation of peripheral immune cells and increase in pro-inflammatory cytokines, such as IL-1β, in AD patient's brain [21,[141][142][143][144].…”

Section: Bbb As a Target Of Systemic Inflammation: Importance To Alzheimer's Disease Developmentmentioning

confidence: 99%

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Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

Oliveira

Kucharska

Garcez

et al. 2021

Cells

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Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood–brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD.

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Section: Bbb As a Target Of Systemic Inflammation: Importance To Alzheimer's Disease Developmentmentioning

confidence: 99%

Section: Bbb As a Target Of Systemic Inflammation: Importance To Alzheimer's Disease Developmentmentioning

confidence: 99%

Section: Bbb As a Target Of Systemic Inflammation: Importance To Alzheimer's Disease Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

Oliveira

Kucharska

Garcez

et al. 2021

Cells

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“…Specifically, in AD, BBB breakdown is correlated with amyloid-β (Aβ) protein accumulation on the vascular walls and the reduction in pericyte coverage [12,84,85]. Interestingly, increased BBB permeability, which can be measured in vivo using several techniques (PET, MRI, near-infrared time-domain optical imaging) [86] correlates well with cognitive decline in humans [87][88][89], and may actually precede it. Furthermore, the expression of transporters, tight junction proteins, and membrane transport regulators is also altered in AD [12,90], suggesting that multiple aspects of BBB function are affected during the course of the disease.…”

Section: Pathophysiologymentioning

confidence: 99%

Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature

Maurissen

Pavlou

Bichsel

et al. 2022

JPM

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Blood-neural barriers regulate nutrient supply to neuronal tissues and prevent neurotoxicity. In particular, the inner blood-retinal barrier (iBRB) and blood–brain barrier (BBB) share common origins in development, and similar morphology and function in adult tissue, while barrier breakdown and leakage of neurotoxic molecules can be accompanied by neurodegeneration. Therefore, pre-clinical research requires human in vitro models that elucidate pathophysiological mechanisms and support drug discovery, to add to animal in vivo modeling that poorly predict patient responses. Advanced cellular models such as microphysiological systems (MPS) recapitulate tissue organization and function in many organ-specific contexts, providing physiological relevance, potential for customization to different population groups, and scalability for drug screening purposes. While human-based MPS have been developed for tissues such as lung, gut, brain and tumors, few comprehensive models exist for ocular tissues and iBRB modeling. Recent BBB in vitro models using human cells of the neurovascular unit (NVU) showed physiological morphology and permeability values, and reproduced brain neurological disorder phenotypes that could be applicable to modeling the iBRB. Here, we describe similarities between iBRB and BBB properties, compare existing neurovascular barrier models, propose leverage of MPS-based strategies to develop new iBRB models, and explore potentials to personalize cellular inputs and improve pre-clinical testing.

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“…Accumulation of amyloid ß (Aß) deposits around cerebral vasculature is thought to be both a cause and consequence of this BBB impairment 19,20 . Despite the evidence that BBB impairment contributes to AD pathogenesis and progression 21,22 , precise transcriptional changes in the GVU in AD, molecular interactions between brain vascular cells and astrocytes, and the correlations of their transcriptome changes with AD neuropathology at the single cell level remain to be established.…”

Section: Introductionmentioning

confidence: 99%

Single Nuclei Transcriptome Reveals Perturbed Brain Vascular Molecules in Alzheimer’s Disease

İş

Wang

Patel

et al. 2021

Preprint

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Blood-brain barrier (BBB) dysfunction is well-known in Alzheimer's disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand the transcriptional changes in brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains resulting in 79,751 nuclei, 4,604 of which formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge-based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the gliovascular unit (GVU) of the BBB. Vascular targets predicted to interact with astrocytic ligands have biological functions in signaling, angiogenesis, amyloid β metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. Our findings provide information on transcriptional changes in predicted vascular-astrocytic partners at the GVU, bringing insights to the molecular mechanisms of BBB breakdown in AD.

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Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

Cited by 98 publications

References 170 publications

Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature

Single Nuclei Transcriptome Reveals Perturbed Brain Vascular Molecules in Alzheimer’s Disease

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