Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease

Vandendriessche, Charysse; Balusu, Sriram; Cauwenberghe, Caroline Van; Brkic, Marjana; Pauwels, Marie J.; Plehiers, Nele; Bruggeman, Arnout; Dujardin, P; Imschoot, Griet Van; Wonterghem, Elien Van; Hendrix, An; Baeke, Femke; Rycke, Riet De; Gevaert, Kris; Vandenbroucke, Roosmarijn E.

doi:10.1186/s40478-021-01245-z

Cited by 38 publications

(36 citation statements)

References 115 publications

(132 reference statements)

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“…In agreement with this, both TNFR1 deficiency and treatment with a TNFR1 inhibitor prevented the Aβ-induced cognitive decline ( 196 ). Additionally, also treatment with an inhibitor of EV production had the same effect ( 195 ). Based on these results, it is tempting to speculate that the combined effect of systemic inflammation and the presence of Aβ might further worsen AD disease progression among others via specific mechanisms at the blood-CSF barriers, such as loss of barrier integrity and EV release, which on their turn further aggravate neuroinflammation.…”

Section: Systemic Inflammation Affects Different Characteristics Of Ad Pathologymentioning

confidence: 94%

“…As mentioned above, systemic inflammation not only has an impact on the integrity of the BBB, but LPS-induced systemic inflammation in mice also disrupts the blood-CSF barrier ( 47 , 177 ) and induces the release of extracellular vesicles (EVs) ( 32 ); both resulting in increased neuroinflammation. Interestingly, also Aβ on its own has a direct impact on the blood-CSF barrier: induction of morphological changes of the CPE cells, decreased expression of TJ components, loss of barrier integrity, and EV release into the CSF ( 47 , 194 , 195 ). Analysis of human gene expression data comparing control and AD patient choroid plexus tissue revealed that TNF/TNFR1 signaling was upregulated in AD suggesting an involvement of this pathway in the blood-CSF barrier associated changes in AD ( 196 ).…”

Section: Systemic Inflammation Affects Different Characteristics Of Ad Pathologymentioning

confidence: 99%

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The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

2022

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Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which the therapeutic effect is not yet conclusively proven, only symptomatic medication that is effective for some AD patients is available. In order to be able to design more rational and effective treatments, our understanding of the mechanisms behind the pathogenesis and progression of AD urgently needs to be improved. Over the last years, it became increasingly clear that peripheral inflammation is one of the detrimental factors that can contribute to the disease. Here, we discuss the current understanding of how systemic and intestinal (referred to as the gut-brain axis) inflammatory processes may affect brain pathology, with a specific focus on AD. Moreover, we give a comprehensive overview of the different preclinical as well as clinical studies that link peripheral Inflammation to AD initiation and progression. Altogether, this review broadens our understanding of the mechanisms behind AD pathology and may help in the rational design of further research aiming to identify novel therapeutic targets.

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Section: Systemic Inflammation Affects Different Characteristics Of Ad Pathologymentioning

confidence: 94%

Section: Systemic Inflammation Affects Different Characteristics Of Ad Pathologymentioning

confidence: 99%

The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

2022

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“…To address this, we prepared choroid plexus explants from NPC1 −/− and NPC1 +/+ mice of 9 weeks and purified EVs from the choroid plexus explant supernatant via size exclusion chromatography (Figure 5A). The quality of the EV fractions were verified as we reported before (Vandendriessche et al, 2021) and according to the MISEV18 guidelines (Thery et al, 2018). Next, purified EVs were transferred to mixed cortical cultures (MCCs) of NPC1 +/+ mice and 24 h later, both MCC cells and cell supernatant were analyzed.…”

Section: Extracellular Vesicles In Cerebrospinalmentioning

confidence: 99%

“…Choroid plexus explants were prepared as we described previously (Balusu et al, 2016b;Vandendriessche et al, 2021). In short, 9 weeks old NPC1 +/+ and NPC1 −/− mice were anesthetized and transcardially perfused with serum free DMEM-F12 medium (11320074; Gibco) after which the choroid plexus (CP) tissue was dissected.…”

Section: Choroid Plexus Explantsmentioning

confidence: 99%

Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

Hoecke

Cauwenberghe

Dominko

et al. 2021

Front. Cell. Neurosci.

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Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.

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“…The strong endocytic activity at the blood–CSF barrier is probably related to the extensive metabolic and synthetic functions of the CP [ 36 ]. Moreover, our research group identified the implication of CP derived EVs in blood to brain communication [ 38 ] and the importance of CP-mediated EV release in AD pathogenesis [ 39 ]. Furthermore, also signaling of CP derived EVs to neuronal stem cells (NSCs) in the brain neurogenic niche via miR-204 was reported [ 40 ].…”

Section: Barriers In Brain Drug Deliverymentioning

confidence: 99%

Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain

2021

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The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain. An increasing amount of data suggests that extracellular vesicles (EVs), i.e., membrane derived vesicles that inherently protect and transfer biological cargoes between cells, naturally cross the CNS barriers. Moreover, EVs can be engineered with targeting ligands to obtain enriched tissue targeting and delivery capacities. In this review, we provide a detailed overview of the literature describing a natural and engineered CNS targeting and therapeutic efficiency of different cell type derived EVs. Hereby, we specifically focus on peripheral administration routes in a broad range of CNS diseases. Furthermore, we underline the potential of research aimed at elucidating the vesicular transport mechanisms across the different CNS barriers. Finally, we elaborate on the practical considerations towards the application of EVs as a brain drug delivery system.

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Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease

Cited by 38 publications

References 115 publications

The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain

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