Amyloid Beta 25–35 induces blood-brain barrier disruption in vitro

Cuevas, Elvis; Rosas-Hernández, Héctor; Burks, Susan M.; Ramirez-Lee, Manuel Alejandro; Guzmán, Adrián; Imam, Syed Z.; Ali, Syed F.; Sarkar, Sumit

doi:10.1007/s11011-019-00447-8

Cited by 42 publications

(33 citation statements)

References 68 publications

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“…Prior studies have demonstrated a loss of expression of ZO-1 in in vitro human and mouse models examining the effects of amyloid beta protein on the BBB, suggesting that this process may occur in Alzheimer's disease 32,33 . Therefore, our results showing modification of the expression of the TJs are similar to those prior findings which implied loss of permeability in neurodegenerative disease 32,34 . The role of claudin-5 in such BBB dysfunction has been less recognized, but alteration of such TJ protein expression could be also interpreted as a complementary frailty of the physical properties of the barrier 35 .…”

Section: Discussionsupporting

confidence: 92%

Sera of elderly obstructive sleep apnea patients alter blood–brain barrier integrity in vitro: a pilot study

Voirin

Celle

Perek

et al. 2020

Sci Rep

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Obstructive sleep apnea syndrome (OSAS) is characterized by repeated episodes of hypoxia during the night. The severity of the disorder can be evaluated using an apnea–hypopnea index (AHI). The physiological consequences are mainly cardiovascular and neuronal dysfunctions. One hypothesis to explain such associated neurological disorders is disruption of the blood–brain barrier (BBB), which protects the brain from endovascular cytotoxic compounds. We selected two subgroups of volunteers from the PROOF cohort study (France), a group of patients suffering newly diagnosed severe OSAS (AHI > 30/h) and a group showing no sleep apnea (AHI < 5/h). We exposed a human in vitro BBB model of endothelial cells (HBEC-5i) with sera of patients with and without OSAS. After exposure, we measured the apparent BBB permeability as well as tight junction and ABC transporter expression using whole cell ELISA. We showed that after incubation with sera from OSAS patients, there was a loss of integrity in the human in vitro BBB model; this was reflected by an increase in permeability (43%; p < 0.001) and correlated with a 50% and 40% decrease in tight junction protein expression of ZO-1 and claudin-5, respectively. At the same time, we observed an upregulation in Pgp protein expression (52%) and functionality, and a downregulation in BCRP expression (52%). Our results demonstrated that severe BBB disorder after exposure to sera from OSAS patients was reflected by an opening of the BBB.

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Section: Discussionsupporting

confidence: 92%

Sera of elderly obstructive sleep apnea patients alter blood–brain barrier integrity in vitro: a pilot study

Voirin

Celle

Perek

et al. 2020

Sci Rep

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“…Therefore in our study, we chose concentrations of soluble amyloid-β observed in brain homogenates and CSF (cerebrospinal fluid) of AD subjects that are ranging from nanomoles [46,47] to micromoles [47][48][49][50]. Concentrations of 1 nM and 1 μM, respectively, were selected due to the neurotrophic properties of nanomolar concentrations of Aβ 25-35 [51] and reported (dose-dependent) neurotoxicity of micromolar concentrations [52,53].…”

Section: Discussionmentioning

confidence: 99%

Protective Activity of Aβ on Cell Cultures (PC12 and THP-1 after Differentiation) Preincubated with Lipopolysaccharide (LPS)

Wiatrak

Balon

2020

Mol Neurobiol

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Amyloid-β (Aβ), the influence of which is considered the pathomechanism of Alzheimer’s disease, is also present in healthy people. The microbiome’s impact is also taken into account, where bacterial lipopolysaccharide (LPS) activates inflammatory processes and stimulates microglia via TLRs. Molecules of bacterial origin can co-create senile plaques with Aβ. This study evaluated the activity of physiological Aβ concentrations on neuronal and microglial cells after preincubation with LPS. Two cell lines were used in the study: PC12 cells differentiated with NGF and THP-1 cells differentiated with phorbol 12-myristate 13-acetate (PMA). Cells were incubated with LPS at concentrations of 1–100 μM for 24 h and then with Aβ25–35 at a concentration of 0.001 μM or 1.0 μM for another 24 h. The viability of the culture and free oxygen radicals and the number of DNA strand breaks in both cell lines were evaluated. Additionally, for PC12 cells, neural features were assessed. Stimulation of repair processes in the presence of Aβ was observed for both studied cell lines. There was a decrease in free radical level and DNA damage number compared to control cultures (cells treated with LPS and without Aβ). The neurotrophic activity of Aβ was observed—the effect on neurites’ growth even after the preincubation of PC12 cells with LPS. At the lowest concentration of LPS used, the increase in neurite length was about 50% greater than in the negative control. At low concentrations, Aβ has a protective effect on neuron-like PC12 cells pretreated with LPS.

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“…It would also be worthwhile to examine the preventive effect of NX210c on early vascular dysfunctions, such as BBB breakdown, pericyte loss or perfusion deficits, which can initiate amyloid and tau pathogenic cascades (Montagne et al, 2015(Montagne et al, , 2017Nation et al, 2019). Indeed, one hypothesis is that NX210 and NX210c may have prevented Aβ 25−35 oligomer-induced BBB dysfunction, as described previously in vitro and in vivo in the mouse model used in this study (Kook et al, 2012;Chumakov et al, 2015;Wan et al, 2015;Miranda-Azpiazu et al, 2018;Cuevas et al, 2019). This may have led to a halt in the progression of AD and cognitive deficits.…”

Section: Discussionmentioning

confidence: 69%

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease

Douce¹,

Delétage²,

Bourdès³

et al. 2021

Front. Neurosci.

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Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e., acetylcholinesterase inhibitors such as donepezil), all of which are limited to the symptomatic control of AD and are associated with side effects that may result in discontinuation of treatment. Therefore, there is an urgent need to develop disease-modifying treatments to prevent AD-induced cognitive deficits. Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis and has a substantial impact on neuronal development. In the current study, we sought to evaluate the protective effects of the linear (NX210) and cyclized (NX210c) forms of a SCO-spondin-derived peptide on learning and memory in a mouse model of AD. Mice received an intracerebroventricular injection of Aβ25–35 oligomers and were subsequently treated with intraperitoneal injections of vehicle, NX210 or NX210c of different doses (ranging from 0.1 to 30 mg/kg) and therapy paradigms (early or late stand-alone treatments, combination with donepezil or second-line treatment). Cognitive function was evaluated using Y-Maze, step-through latency passive avoidance (STPA) and Morris water maze (MWM) tests for up to 4 months. Early stage daily treatment with NX210 and NX210c decreased the levels of common pathological markers and features of AD, including Aβ1–42, phosphorylated-tau, inflammation, astrogliosis and lipid peroxidation. Meanwhile, use of these drugs increased the levels of synaptophysin and postsynaptic density protein 95. Regardless of the experimental paradigm used, NX210 and NX210c prevented Aβ25–35-induced decrease in spontaneous alternations (Y-Maze) and step-through latency into the dark compartment (STPA), and Aβ25–35-induced increase in time needed to locate the immersed platform during the learning phase and decrease in time spent in the target quadrant during the retention phase (MWM). Interestingly, this study provides the novel evidence that the native and oxidized cyclic forms of the SCO-spondin-derived peptide reduce pathological factors associated with AD and restore learning and memory at both early and late disease stages. Overall, this study sheds light on the therapeutic potential of this innovative disease-modifying peptide to restore memory function in patients with AD.

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Amyloid Beta 25–35 induces blood-brain barrier disruption in vitro

Cited by 42 publications

References 68 publications

Sera of elderly obstructive sleep apnea patients alter blood–brain barrier integrity in vitro: a pilot study

Sera of elderly obstructive sleep apnea patients alter blood–brain barrier integrity in vitro: a pilot study

Protective Activity of Aβ on Cell Cultures (PC12 and THP-1 after Differentiation) Preincubated with Lipopolysaccharide (LPS)

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease

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