Alpha synuclein is transported into and out of the brain by the blood–brain barrier

Sui, Yu Ting; Bullock, Kristin M.; Erickson, Michelle A.; Zhang, Jing; Banks, William A.

doi:10.1016/j.peptides.2014.09.018

Cited by 163 publications

(136 citation statements)

References 60 publications

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“…Interestingly, experimental studies suggest that α-synuclein is transported into and out of the brain across the BBB as a free peptide 235 . Moreover, systemically administered α-synuclein oligomers, ribbons and fibrils cause distinct synucleinopathies, implying that they can all cross the BBB 236 .…”

Section: Bbb Breakdown and Neurodegenerationmentioning

confidence: 99%

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

2018

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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, post-mortem tissue and 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 BBB are presented.

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Section: Bbb Breakdown and Neurodegenerationmentioning

confidence: 99%

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

2018

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“…Although aSyn expression has been identified in several extracerebral tissues including erythrocytes, there are data suggesting that CSF aSyn predominantly derives from neurons of the CNS . However, it is still unclear if the CSF derived from the plexus already contains aSyn from the peripheral blood . Blood‐derived aSyn might be important if the blood‐brain barrier is compromised, especially in light of experimental data demonstrating that peripherally injected aSyn readily reaches the brain in mice …”

Section: Suggested Standard Operating Procedures (Modified From Refermentioning

confidence: 99%

A user's guide for α‐synuclein biomarker studies in biological fluids: Perianalytical considerations

et al. 2017

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Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total α‐synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods. We also discuss analytical confounders. We identify gaps in the knowledge and delineate specific areas that require further investigation, such as the need to identify posttranslational modifications of α‐synuclein and antibody‐independent reference methods for quantification, as well as the analysis of potential confounders, such as comorbidities, medication, and phenotypes of Parkinson's disease in larger cohorts. This review could be used as a guideline for future Parkinson's disease biomarker studies and will require regular updating as more information arises in this growing field, including new technical developments as they become available. In addition to reviewing best practices, we also identify the current technical limitations and gaps in the knowledge that should be addressed to enable accurate and quantitative assessment of α‐synuclein levels in the clinical setting. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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“…117 Furthermore, it was recently demonstrated that human αSYN introduced into the intestinal wall of rats could migrate up the vagus nerve to the dorsal motor nucleus in the brainstem. 6 This translocation was mediated by microtubule-associated transport in neurons, and it was observed equally for monomeric, oligomeric, and fibrillar forms of αSYN.…”

Section: Introductionmentioning

confidence: 99%

The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis?

Houser

Tansey

2017

npj Parkinson's Disease

437

348

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The state of the intestinal environment can have profound effects on the activity of the central nervous system through the physiological contributions of the microbiota, regulation of intestinal barrier function, and altered activity of peripheral neurons. The common language employed for much of the gut-brain communication is the modulation of immune activity. Chronic proinflammatory immune activity is increasingly being recognized as a fundamental element of neurodegenerative disorders, and in Parkinson’s disease, inflammation in the intestine appears particularly relevant in pathogenesis. We review the evidence that intestinal dysfunction is present in Parkinson’s disease and that it may reflect the earliest manifestations of Parkinson’s disease pathology, and we link these findings to dysregulated immune activity. Based on this, we present a model for Parkinson’s disease pathogenesis in which the disorder originates in the intestine and progresses with inflammation as its underlying mechanism. More in-depth investigations into the physiological mechanisms underlying peripheral pre-motor symptoms in Parkinson’s disease are expected to lead to the development of novel diagnostic and therapeutic measures that can slow or limit progression of the disease to more advanced stages involving debilitating motor and cognitive symptoms.

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Alpha synuclein is transported into and out of the brain by the blood–brain barrier

Cited by 163 publications

References 60 publications

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

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

A user's guide for α‐synuclein biomarker studies in biological fluids: Perianalytical considerations

The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis?

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