Immortalised Hippocampal Astrocytes from 3xTG-AD Mice Fail to Support BBB Integrity In Vitro: Role of Extracellular Vesicles in Glial-Endothelial Communication

Kriaučiūnaitė, Karolina; Kaušylė, Aida; Pajarskienė, Justina; Tunaitis, Virginijus; Lim, Dmitry; Verkhratsky, Alexei

doi:10.1007/s10571-020-00871-w

Cited by 28 publications

(16 citation statements)

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“…The effects of these changes, in turn, may have multiple consequences, e.g., we recently have shown that conditioned medium from 3xTg-AD astrocytes reduces synaptic proteins in cultured neurons 50 , while 3Tg-iAstros fail to support the integrity of the blood-brain barrier in vitro 51 . In light of this, our work exemplifies the importance of multidisciplinary approach in studying such complex phenomena as AD and illustrates the use of iAstro cells as versatile and cost-effective astrocytic cellular model of AD.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

et al. 2020

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The pathogenesis of Alzheimer's disease (AD), a slowly-developing age-related neurodegenerative disorder, is a result of the action of multiple factors including deregulation of Ca 2+ homeostasis, mitochondrial dysfunction, and dysproteostasis. Interaction of these factors in astrocytes, principal homeostatic cells in the central nervous system, is still poorly understood. Here we report that in immortalized hippocampal astrocytes from 3xTg-AD mice (3Tg-iAstro cells) bioenergetics is impaired, including reduced glycolysis and mitochondrial oxygen consumption, and increased production of reactive oxygen species. Shotgun proteomics analysis of mitochondria-ER-enriched fraction showed no alterations in the expression of mitochondrial and OxPhos proteins, while those related to the ER functions and protein synthesis were deregulated. Using ER-and mitochondria-targeted aequorin-based Ca 2+ probe we show that, in 3Tg-iAstro cells, ER was overloaded with Ca 2+ while Ca 2+ uptake by mitochondria upon ATP stimulation was reduced. This was accompanied by the increase in short distance (≈8-10 nm) contact area between mitochondria and ER, upregulation of ER-stress/unfolded protein response genes Atf4, Atf6 and Herp, and reduction of global protein synthesis rate. We suggest that familial AD mutations in 3Tg-iAstro cells induce mitochondria-ER interaction changes that deregulate astrocytic bioenergetics, Ca 2+ homeostasis and proteostasis. These factors may interact, creating a pathogenic loop compromising homeostatic and defensive functions of astroglial cells predisposing neurons to dysfunction.

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

et al. 2020

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“…Ultrastructural studies of the BBB in aged rats showed increased thickness of capillary walls and basement membranes; furthermore, in the old animal the area of the astrocyte endfeet surrounding the capillaries was significantly higher than in the young animal [17]. There are also some indications that astrocytes loos their ability to regulate tight junctions expression in the context of neurodegeneration [94]; whether a similar loss of function occurs in physiological ageing remains to be investigated. In conclusion, brain ageing is accompanied by progressive decline in the BBB deterioration and accumulating evidence indicate that astroglial dysfunction plays complex and multifaceted role in this process.…”

Section: Neurogliovascular Unit and The Blood-brain Barriermentioning

confidence: 99%

Astroglial asthenia and loss of function, rather than reactivity, contribute to the ageing of the brain

Verkhratsky

Augusto-Oliveira

Pivoriūnas

et al. 2020

Pflugers Arch - Eur J Physiol

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Astroglia represents a class of heterogeneous, in form and function, cells known as astrocytes, which provide for homoeostasis and defence of the central nervous system (CNS). Ageing is associated with morphological and functional remodelling of astrocytes with a prevalence of morphological atrophy and loss of function. In particular ageing is associated with (i) decrease in astroglial synaptic coverage; (ii) deficits in glutamate and potassium clearance; (iii) reduced astroglial synthesis of synaptogenic factors such as cholesterol; (iv) decrease in aquaporin 4 channels in astroglial endfeet with subsequent decline in the glymphatic clearance; (v) decrease in astroglial metabolic support through the lactate shuttle; (vi) decreased adult neurogenesis resulting from diminished proliferative capacity of radial stem astrocytes; (vii) decline in the astroglial-vascular coupling and deficient blood-brain barrier and (viii) decrease in astroglial ability to mount reactive astrogliosis. Decrease in reactive capabilities of astroglia is associated with increase in age-dependent neurodegenerative diseases. Astroglial morphology and function can be influenced and improved by lifestyle interventions such as intellectual engagement, social interactions physical exercise, caloric restriction, and healthy diet. These modifications of lifestyle are paramount for cognitive longevity.

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“…As mentioned above, the biogenesis of MVs is not satisfactorily understood ( You and Ikezu, 2019 ). The design of sound cell culture models is challenging, especially when investigating the interaction of different cell types in the brain, but it has been achieved ( Pascua-Maestro et al, 2018 ; Gharbi et al, 2020 ; Kriaučiūnaitė et al, 2021 ). To gain insights into synaptophysin-bearing MVs in AD that are applicable to in vivo conditions, cell culture models of human AD neurons, which do not currently exist, are needed.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid of Patients With Alzheimer’s Disease Contains Increased Percentages of Synaptophysin-Bearing Microvesicles

Utz

Berner

Muñoz

et al. 2021

Front. Aging Neurosci.

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IntroductionIn Alzheimer’s disease, the severity of symptoms is linked to a loss of synaptic density and the spread of pathologically hyperphosphorylated tau. The established cerebrospinal fluid markers Aβ, tau and phospho-tau reflect the histopathological hallmarks of Alzheimer’s disease but do not indicate disease progression. Such markers are of special interest, especially for trials of disease modifying drugs. Microvesicles are produced by stressed cells and reflect part of the metabolism of their cells of origin. Therefore, we investigated microvesicles of neuronal origin in cerebrospinal fluid.Materials and MethodsWe used flow cytometry to analyze microvesicles carrying tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, synaptophysin, and SNAP-25 in the cerebrospinal fluid of 19 patients with Alzheimer’s disease and 15 non-inflammatory neurological disease controls.ResultsThe percentages of synaptophysin-bearing microvesicles were significantly higher in the cerebrospinal fluid of patients with Alzheimer’s disease than in the CSF of non-inflammatory neurological disease controls. Tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, and SNAP-25 did not differ between the groups. The percentages of synaptophysin-bearing vesicles distinguished patients with Alzheimer’s disease from the controls (AUC = 0.81).ConclusionThe loss of synapses in Alzheimer’s disease may be reflected by synaptophysin-bearing microvesicles in the cerebrospinal fluid. Future studies are needed to investigate the possibility of using these MVs as a marker to determine the activity of Alzheimer’s disease.

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Immortalised Hippocampal Astrocytes from 3xTG-AD Mice Fail to Support BBB Integrity In Vitro: Role of Extracellular Vesicles in Glial-Endothelial Communication

Cited by 28 publications

References 40 publications

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

Astroglial asthenia and loss of function, rather than reactivity, contribute to the ageing of the brain

Cerebrospinal Fluid of Patients With Alzheimer’s Disease Contains Increased Percentages of Synaptophysin-Bearing Microvesicles

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