Astrocytes from old Alzheimer's disease mice are impaired in Aβ uptake and in neuroprotection

Iram, Tal; Trudler, Dorit; Kain, David; Kanner, Sivan; Galron, Ronit; Vassar, Robert; Barzilai, Ari; Blinder, Pablo; Fishelson, Zvi; Frenkel, Dan

doi:10.1016/j.nbd.2016.08.001

Cited by 96 publications

(88 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the same model, IFN-γ stimulated BACE1 expression and APP processing by this secretase [4]. Astrocytes from double-transgenic APPswePS1dE9 mice showed a “chronic” activation that coincides with impairment of normal astrocyte function [5], while 5xFAD astrocytes showed reduced Aβ internalization [6]. In the presenilin 1 (PS1) knock-in (PS1 M146V ) mouse model, cultured astrocytes showed an enhanced ceramide-induced apoptosis, in contrast to WTs [7].…”

Section: Introductionmentioning

confidence: 99%

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Gijsel-Bonnello¹,

Baranger²,

Benech³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer’s disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

show abstract

Section: Introductionmentioning

confidence: 99%

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Gijsel-Bonnello¹,

Baranger²,

Benech³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Anti-GFAP-FITC (1: 40) and anti-CD11b-PE antibody (1: 100, Abcam, Cambridge, UK) was added to the blocking solution for 30 min. Finally, the cells were resuspended for flow cytometric analysis [16]. …”

Section: Methodsmentioning

confidence: 99%

Neuroprotective Effects of Pycnogenol Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Primary Rat Astrocytes via NF-κB and ERK1/2 MAPK Pathways

Xia¹,

Ji²,

Zhang³

2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Backgrounds/Aims: Pycnogenol (PYC) is a patented mix of bioflavonoids with potent anti-oxidant and anti-inflammatory properties. In this study, we investigated the effects of PYC on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in primary rat astrocytes. Methods: The primary rat astrocytes were randomly divided into 6 groups, blank control, OGD/R, OGD/R+PYC (10, 20, 40, and 60 µg/mL). The cell activity were detected by MTT and LDH assays, then the levels of oxidant products [malondialdehyde (MDA) and reactive oxygen species (ROS)] , antioxidants [superoxide dismutase (SOD)], mitochondrial membrane potential (MMP) and inflammatory cytokines were detected. In addition, the expression levels of apoptosis-related proteins (Bax, Bcl-2 and Cleaved caspase 3), proinflammatory factors (NF-κB p65), and p-ERK1/2 were measured by Western blot analysis. Results: The results showed that PYC incubation dose-dependently attenuated cell viability loss, LDH leakage, oxidative stress, inflammatory cytokines accumulation and cell apoptosis caused by OGD/R. Furthermore, PYC pretreatment dose-dependently suppressed OGD/R-induced NF-κB p65 nuclear translocation, NF-κB activity and ERK1/2 phosphorylation. Similarly to PYC, NF-κB inhibitor PDTC and ERK1/2 inhibitor PD098059 dramatically inhibited OGD/R-induced NF-κB activation, ERK1/2 phosphorylation, and ROS production, as well as TNF-α secretion. Conclusions: These findings revealed that PYC has neuroprotective effects against OGD/R-induced injury via NF-κB and ERK1/2 pathways in primary rat astrocytes.

show abstract

“…In contrast to the effects on p-tau and GFAP in TauP301L mice, we did not detect any changes in Aβ levels or GFAP in 3x-AβPP mice with pazopanib treatment. Another group has shown increased levels of GFAP in 5xFAD mice and impaired Aβ uptake by aged astrocytes [68]. Moreover, tau is an intracellular protein while Aβ is extracellular.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have shown Aβ-containing astrocytes in AD brains [72-74], and both astrocytes [75] and microglia are capable of degrading Aβ, likely via scavenger receptors [76, 77]. Moreover, an imbalance between complement protein C1q and scavenger receptor B1 has been implicated in impaired uptake of Aβ by astrocytes [68]. These studies focused on Aβ and had little or no mention of tau.…”

Section: Discussionmentioning

confidence: 99%

Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy

Javidnia

Hebron

Xin

et al. 2017

JAD

View full text Add to dashboard Cite

Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies.

show abstract

Astrocytes from old Alzheimer's disease mice are impaired in Aβ uptake and in neuroprotection

Cited by 96 publications

References 70 publications

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Neuroprotective Effects of Pycnogenol Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Primary Rat Astrocytes via NF-κB and ERK1/2 MAPK Pathways

Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy

Contact Info

Product

Resources

About