Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Allen, Barrett D.; Apodaca, Lauren A.; Syage, Amber R.; Markarian, Mineh; Baddour, Al Anoud D.; Minasyan, Harutyun; Alikhani, Leila; Lu, Celine; West, Brian L.; Giedzinski, Erich; Baulch, Janet E.; Acharya, Munjal M.

doi:10.1186/s40478-019-0838-8

Cited by 41 publications

(20 citation statements)

References 53 publications

(116 reference statements)

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“…No adverse effects of PLX5622 treatment were observed on neural stem and oligo-progenitor cell proliferation and differentiation [70,71]. Moreover, treatment with PLX5622 showed neurocognitive benefits and attenuation of neuroinflammation in a chemobrain model [72]. Microglia depletion rescued most radiationinduced cognitive changes observed in our behavioral tests, reduced microglial activation, and restored mature dendritic spines.…”

Section: Discussionmentioning

confidence: 67%

Mitigation of helium irradiation-induced brain injury by microglia depletion

Allen

Syage

Maroso

et al. 2020

J Neuroinflammation

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Background: Cosmic radiation exposures have been found to elicit cognitive impairments involving a wide-range of underlying neuropathology including elevated oxidative stress, neural stem cell loss, and compromised neuronal architecture. Cognitive impairments have also been associated with sustained microglia activation following low dose exposure to helium ions. Space-relevant charged particles elicit neuroinflammation that persists long-term post-irradiation. Here, we investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions. Methods: Adult mice were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia 2 weeks after whole body helium irradiation (4 He, 30 cGy, 400 MeV/n). Cohorts of mice maintained on a normal and PLX5622 diet were tested for cognitive function using seven independent behavioral tasks, microglial activation, hippocampal neuronal morphology, spine density, and electrophysiology properties 4-6 weeks later. Results: PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiated animals on normal diet exhibited a range of behavioral deficits involving the medial prefrontal cortex and hippocampus and increased microglial activation. Animals on PLX5622 diet exhibited no radiation-induced cognitive deficits, and expression of resting and activated microglia were almost completely abolished, without any effects on the oligodendrocyte progenitors, throughout the brain. While PLX5622 treatment was found to attenuate radiation-induced increases in post-synaptic density protein 95 (PSD-95) puncta and to preserve mushroom type spine densities, other morphologic features of neurons and electrophysiologic measures of intrinsic excitability were relatively unaffected. Conclusions: Our data suggest that microglia play a critical role in cosmic radiation-induced cognitive deficits in mice and, that approaches targeting microglial function are poised to provide considerable benefit to the brain exposed to charged particles.

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Section: Discussionmentioning

confidence: 67%

Mitigation of helium irradiation-induced brain injury by microglia depletion

Allen

Syage

Maroso

et al. 2020

J Neuroinflammation

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“…To address this finding, we quantified cytokines in the WT and C1q-Flox brains exposed to cranial RT. Activated microglia and elevated proinflammatory cytokines play a disruptive role in fear memory consolidation (52)(53)(54)(55)(56). Our multiplex data (Fig.…”

Section: Microglial C1q Knockdown Protects Against Cranial Rt-induced Cognitive Deficitsmentioning

confidence: 73%

Glia-Selective Deletion of Complement C1q Prevents Radiation-Induced Cognitive Deficits and Neuroinflammation

et al. 2020

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The adverse neurocognitive sequelae following clinical radiotherapy (RT) for central nervous system (CNS) malignancies are often longlasting without any clinical recourse. Despite recent progress, the cellular mechanisms mediating RT-induced cognitive deficits (RICD) are poorly understood. The complement system is an immediate sensor of a disturbed inflammatory environment and a potent mediator of gliosis with a range of nonimmune functions in the CNS, including synaptic pruning, which is detrimental if dysregulated. We hypothesize that complement-mediated changes in glial cell function significantly contribute to RICD. The underlying alterations in CNS complement cascade proteins (C1q, C3), TLR4, and colabeling with glia (IBA1, GFAP) were examined using gene expression, immunofluorescence, and in silico modeling approaches in the adult mouse brain following 9 Gy cranial RT. Three-dimensional volumetric quantification showed elevated molecular signatures of gliosis at shortand long-term post-RT times. We found significant elevations in complement C1q, C3, and TLR4 post-RT accompanied by increased colabeling of astrocytes and microglia. To address the mechanism of RT-induced complement cascade activation, neuroinflammation, and cognitive dysfunction, we used a genetic approach-conditional, microglia-selective C1q (Flox) knockdown mice-to determine whether a glia-specific, upstream complement cascade contributes to RICD. C1q-Flox mice exposed to cranial RT showed no cognitive deficits compared with irradiated WT mice. Further, irradiated C1q-Flox mice were protected from RT-induced microglial activation and synaptic loss, elevation of anaphylatoxin C5a receptor, astrocytic-C3, and microglial-TLR4 expression in the brain. Our findings demonstrate for the first time a microglia-specific mechanism of RICD involving an upstream complement cascade component, C1q.Significance: Clinically-relevant radiotherapy induces aberrant complement activation, leading to brain injury. Microglia-selective genetic deletion of CNS complement C1q ameliorates radiationinduced cognitive impairments, synaptic loss, and neuroinflammation, highlighting the potential for C1q as a novel therapeutic target.See related commentary by Korimerla and Wahl, p. 1635

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“…Persistent activation of microglia in the AD brain is detrimental for neuronal and cognitive function. Our past data have shown anti-in ammatory effects of stem cells or stem cell-derived EV in clinically relevant irradiation [2,5,14,27] and chemobrain [4,8] models. Substantiating the neuroprotective impact of EV in the AD brain, we found signi cant reductions in the levels of CD68, a marker of microglial/myeloid cell activation.…”

Section: Discussionmentioning

confidence: 93%

Mitigation of Alzheimer’s Disease Neuropathologies by Human Neural Stem Cell-derived Extracellular Vesicles

Apodaca¹,

Baddour²,

Garcia³

et al. 2020

Preprint

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Background: Regenerative therapies to mitigate Alzheimer’s disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EV) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions. Methods: Using the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EV on the neurocognitive and neuropathologic outcomes in the AD brain. Two or six-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EV, respectively.Results: RO treatment using hNSC-derived EV restored fear extinction memory consolidation and reduced anxiety-related behaviors 4-6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function. Conclusions: Collectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EV for remediation of behavioral and molecular AD neuropathologies.

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Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Cited by 41 publications

References 53 publications

Mitigation of helium irradiation-induced brain injury by microglia depletion

Mitigation of helium irradiation-induced brain injury by microglia depletion

Glia-Selective Deletion of Complement C1q Prevents Radiation-Induced Cognitive Deficits and Neuroinflammation

Mitigation of Alzheimer’s Disease Neuropathologies by Human Neural Stem Cell-derived Extracellular Vesicles

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