Increased Release of Apolipoprotein E in Extracellular Vesicles Following Amyloid-β Protofibril Exposure of Neuroglial Co-Cultures

Nikitidou, Elisabeth; Khoonsari, Payam Emami; Shevchenko, Ganna; Ingelsson, Martin; Kultima, Kim; Erlandsson, Anna

doi:10.3233/jad-170278

Cited by 43 publications

(43 citation statements)

References 65 publications

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“…1e) or were left untreated. Similar to our previous findings 8,19,25 , the astrocytes in the co-culture ingested large amounts of Aβ 42 protofibrils, which accumulated intracellularly in lysosomal compartments (Fig. 1f).…”

Section: Endocytosis Of Evs Results In Intracellular Aβ Deposits In Csupporting

confidence: 90%

“…Cell lysis was performed as described previously 19 . In short, cell culture medium was thoroughly removed from the dishes and the cells were lysed in ice-cold lysis buffer (20 mM Tris pH 7.5, 0.5% Triton X-100, 0.5% deoxycholic acid, 150 mM NaCl, 10 mM EDTA, 30 mM NaPyro), supplemented with a protease inhibitor cocktail (ThermoScientific).…”

Section: Cell Lysismentioning

confidence: 99%

“…Western blot analysis was performed as described previously 19 . In short, protein concentrations of the total cell lysates were measured with Pierce BCA protein kit (ThermoFisher Scientific), according to the manufacturer's instructions.…”

Section: Western Blot Analysismentioning

confidence: 99%

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Extracellular vesicles from amyloid-β exposed cell cultures induce severe dysfunction in cortical neurons

Beretta

Nikitidou

Streubel-Gallasch

et al. 2020

Sci Rep

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Alzheimer’s disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-β (Aβ) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of Aβ42 protofibrils by astrocytes results in the release of EVs containing neurotoxic Aβ. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and Aβ42 protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from Aβ42 protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from Aβ exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of Aβ-induced pathology.

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Section: Endocytosis Of Evs Results In Intracellular Aβ Deposits In Csupporting

confidence: 90%

Section: Cell Lysismentioning

confidence: 99%

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Extracellular vesicles from amyloid-β exposed cell cultures induce severe dysfunction in cortical neurons

Beretta

Nikitidou

Streubel-Gallasch

et al. 2020

Sci Rep

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“…Wang et al ( 2012 ) found that the astrocytic-mediated apoptosis is associated with the secretion of PAR-4/ceramide containing exosomes in the adjacent cells even if they were not exposed to Aβ. It has been demonstrated that astrocytes tend to interact more with exosomes and accumulate large amounts of Aβ42 protofibers, subsequently, this storage results in endosomal/lysosomal system alterations which induce exosome secretion with a neurotoxic cargo (Nikitidou et al, 2017 ). Astrocyte-derived exosomes of patients with AD had up to 20-fold higher concentrations of β/γ-secretase and sAPPβ than neuron-derived exosomes (Goetzl et al, 2016 ).…”

Section: Alzheimer’s Diseasementioning

confidence: 99%

Potential Effects of MSC-Derived Exosomes in Neuroplasticity in Alzheimer’s Disease

Reza-Zaldívar

Hernández-Sapiéns

Minjarez

et al. 2018

Front. Cell. Neurosci.

124

103

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Alzheimer’s disease (AD) is the most common type of dementia affecting regions of the central nervous system that exhibit synaptic plasticity and are involved in higher brain functions such as learning and memory. AD is characterized by progressive cognitive dysfunction, memory loss and behavioral disturbances of synaptic plasticity and energy metabolism. Cell therapy has emerged as an alternative treatment of AD. The use of adult stem cells, such as neural stem cells and Mesenchymal Stem Cells (MSCs) from bone marrow and adipose tissue, have the potential to decrease cognitive deficits, possibly by reducing neuronal loss through blocking apoptosis, increasing neurogenesis, synaptogenesis and angiogenesis. These processes are mediated primarily by the secretion of many growth factors, anti-inflammatory proteins, membrane receptors, microRNAs (miRNA) and exosomes. Exosomes encapsulate and transfer several functional molecules like proteins, lipids and regulatory RNA which can modify cell metabolism. In the proteomic characterization of the content of MSC-derived exosomes, more than 730 proteins have been identified, some of which are specific cell type markers and others are involved in the regulation of binding and fusion of exosomes with adjacent cells. Furthermore, some factors were found that promote the recruitment, proliferation and differentiation of other cells like neural stem cells. Moreover, within exosomal cargo, a wide range of miRNAs were found, which can control functions related to neural remodeling as well as angiogenic and neurogenic processes. Taking this into consideration, the use of exosomes could be part of a strategy to promote neuroplasticity, improve cognitive impairment and neural replacement in AD. In this review, we describe how exosomes are involved in AD pathology and discuss the therapeutic potential of MSC-derived exosomes mediated by miRNA and protein cargo.

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“…Neurodegenerative diseases, including AD, are defined by loss of brain homeostasis, which at least partly could be due to the severely stressed astrocytes that are unable to fulfil their nor-mal tasks [58]. Our previous studies indicate that astrocytes play a central role in the progression of AD, by accumulating and spreading toxic A␤ species [42,59]. Interestingly, it was recently shown that wild type rats subjected to CCI, displayed several-fold increased MHCII expression as well as accumulation of phosphorylated tau and A␤PP 6 months later [60].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer’s Disease

Zyśk

Clausen

Aguilar

et al. 2019

JAD

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Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12-and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-␤ (A␤) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A␤ pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

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Increased Release of Apolipoprotein E in Extracellular Vesicles Following Amyloid-β Protofibril Exposure of Neuroglial Co-Cultures

Cited by 43 publications

References 65 publications

Extracellular vesicles from amyloid-β exposed cell cultures induce severe dysfunction in cortical neurons

Extracellular vesicles from amyloid-β exposed cell cultures induce severe dysfunction in cortical neurons

Potential Effects of MSC-Derived Exosomes in Neuroplasticity in Alzheimer’s Disease

Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer’s Disease

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