Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

Montagne, Axel; Zhao, Zhen; Zloković, Berislav V.

doi:10.1084/jem.20171406

Cited by 522 publications

(486 citation statements)

References 198 publications

(292 reference statements)

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“…By contrast, individuals homozygous for the most common allele, APOE*ε3, have a reduced risk of AD and show a decreased degree of BBB breakdown 147,152,156,158 . As reviewed elsewhere 11 , multiple experimental studies have confirmed that BBB breakdown causes capillary leakage in AD models of β-amyloidosis 159–162 and in APOE*ε4 transgenic mice 71,163,164 .…”

Section: Postmortem Evidence Of Bbb Disruptionmentioning

confidence: 83%

“…Most mechanistic insights have been gained from animal models of these disorders 6,11 . However, the development of advanced neuroimaging techniques that are capable of interrogating changes in BBB integrity in humans in regions as small as hippocampal subfields 46,49,65,66 , and improved imaging techniques for determining regional cerebral blood flow and haemodynamic responses 2 , enlarged perivascular spaces 55 , and incidence and distribution of microbleeds, using high strength 7T magnets to increase the detectability of these vascular changes 87,104 , hold considerable promise for future neurovascular research in humans.…”

Section: Resultsmentioning

confidence: 99%

“…Fibrin(ogen) deposits around capillaries were also found in brain tissue from patients with HD 60 . Fibrinogen, thrombin, IgG and haemosiderin deposits have been found in brain and spinal cord tissue from patients with sporadic or familial forms of ALS 62,107,168 as well as in a transgenic mouse model of ALS, prior to the onset of motor neuron degeneration 11,169 .…”

Section: Postmortem Evidence Of Bbb Disruptionmentioning

confidence: 99%

“…Finally, we discuss future directions, gaps in the field, and opportunities to control neurological disease by targeting the BBB. This Review does not examine the role of reduced cerebral blood flow and altered haemodynamic responses in AD and neurodegenerative disorders, nor does it cover BBB disruption in experimental models of AD and neurodegeneration, which have been extensively reviewed elsewhere 2,3,9,11 .…”

Section: Introductionmentioning

confidence: 99%

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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: Postmortem Evidence Of Bbb Disruptionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Postmortem Evidence Of Bbb Disruptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2018

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“…Several authors have reported reduced expression of adhesion molecules and tight junction proteins in BBB endothelial cells combined with a dysfunctional and/or disrupted neurovascular unit in AD patients with early disease long before the occurrence of dementia and in the absence of neurodegeneration and brain atrophy [382][383][384]. Importantly, such damage may result from the presence of prolonged systemic inflammation and elevated levels of PICs, which increase the permeability of tight junctions by decreasing levels of glycocalyx and other adhesion molecules, as well as causing endothelial cell damage and disruption of the of glia limitans [385,386].…”

Section: The Function Of the Bbb In This Modelmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death

Tessier,

Cortese,

Yuan

et al. 2024

JAMA Netw Open

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ImportanceAge-standardized dementia mortality rates are on the rise. Whether long-term consumption of olive oil and diet quality are associated with dementia-related death is unknown.ObjectiveTo examine the association of olive oil intake with the subsequent risk of dementia-related death and assess the joint association with diet quality and substitution for other fats.Design, Setting, and ParticipantsThis prospective cohort study examined data from the Nurses’ Health Study (NHS; 1990-2018) and Health Professionals Follow-Up Study (HPFS; 1990-2018). The population included women from the NHS and men from the HPFS who were free of cardiovascular disease and cancer at baseline. Data were analyzed from May 2022 to July 2023.ExposuresOlive oil intake was assessed every 4 years using a food frequency questionnaire and categorized as (1) never or less than once per month, (2) greater than 0 to less than or equal to 4.5 g/d, (3) greater than 4.5 g/d to less than or equal to 7 g/d, and (4) greater than 7 g/d. Diet quality was based on the Alternative Healthy Eating Index and Mediterranean Diet score.Main Outcome and MeasureDementia death was ascertained from death records. Multivariable Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% CIs adjusted for confounders including genetic, sociodemographic, and lifestyle factors.ResultsOf 92 383 participants, 60 582 (65.6%) were women and the mean (SD) age was 56.4 (8.0) years. During 28 years of follow-up (2 183 095 person-years), 4751 dementia-related deaths occurred. Individuals who were homozygous for the apolipoprotein ε4 (APOE ε4) allele were 5 to 9 times more likely to die with dementia. Consuming at least 7 g/d of olive oil was associated with a 28% lower risk of dementia-related death (adjusted pooled HR, 0.72 [95% CI, 0.64-0.81]) compared with never or rarely consuming olive oil (P for trend &lt; .001); results were consistent after further adjustment for APOE ε4. No interaction by diet quality scores was found. In modeled substitution analyses, replacing 5 g/d of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8% (95% CI, 4%-12%) to 14% (95% CI, 7%-20%) lower risk of dementia mortality. Substitutions for other vegetable oils or butter were not significant.Conclusions and RelevanceIn US adults, higher olive oil intake was associated with a lower risk of dementia-related mortality, irrespective of diet quality. Beyond heart health, the findings extend the current dietary recommendations of choosing olive oil and other vegetable oils for cognitive-related health.

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Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

Cited by 522 publications

References 198 publications

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

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

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death

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