Progesterone attenuates Aβ 25–35 -induced neuronal toxicity via JNK inactivation and progesterone receptor membrane component 1-dependent inhibition of mitochondrial apoptotic pathway

Qin, Yabin; Chen, Zesha; Han, Xiaolei; Wu, Honghai; Yu, Yang; Wu, Jie; Li, Sha; Yan-ning, Hou

doi:10.1016/j.jsbmb.2015.01.002

Cited by 53 publications

(37 citation statements)

References 52 publications

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“…Moreover, Sig2R/PGRMC1 signaling has been implicated in cellular processes relevant to CNS diseases, including neuroprotection, axonal migration, and mitochondrial protection (Cahill ; Qin et al . ). For example, progesterone, which binds to both Sig2R and PGRMC1 (Chu et al .…”

mentioning

confidence: 97%

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

Sahn

Ardestani

et al. 2017

Journal of Neurochemistry

154

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Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R binding ligands and their cellular and in vivo activity in experimental models of Alzheimer’s disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells. The Sig2R antagonists SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), it indicates that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPPLond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD.

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mentioning

confidence: 97%

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

Sahn

Ardestani

et al. 2017

Journal of Neurochemistry

154

View full text Add to dashboard Cite

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“…However, its oncogenic actions are due in part to its ability to promote cell survival and inhibit apoptosis. PGRMC1 is thought to mediate the protective effects of progesterone on rats modeling Alzheimer’s disease via inhibition of the mitochondrial apoptotic mechanism[38]. It has also shown to be an important mediator in the neuro-protective effect of a synthetic progesterone in the degenerative eye disease retinitis pigmentosa[39].…”

Section: Discussionmentioning

confidence: 99%

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

et al. 2017

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The term “motor neuron disease” encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers, and demonstrated SNCA is a modifier of pathology in motor neuron disease.

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“…61) Caspase 3 is involved in the cleavage of amyloid-beta precursor protein (APP), which is associated with neuronal death in AD. 62) Targeted inhibition of Caspase-3 by Ost may attenuate Aβ-induced apoptosis, 63,64) and may be a new therapeutic for preventing neuronal apoptosis and inhibiting progression of AD.…”

Section: Discussionmentioning

confidence: 99%

The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice

Kong

Yao

et al. 2015

Biological & Pharmaceutical Bulletin

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It is believed that neuronal death caused by abnormal deposition of amyloid-beta peptide is the major cause of the cognitive decline in Alzheimer's disease. Adult neurogenesis plays a key role in the rescue of impaired neurons and amelioration of cognitive impairment. In the present study, we demonstrated that osthole, a natural coumarin derivative, was capable of promoting neuronal stem cell (NSC) survival and inducing NSC proliferation in vitro. In osthole-treated APP/PS1 transgenic mice, a significant improvement in learning and memory function was seen, which was associated with a significant increase in the number of new neurons (Ki67 /NF-M ) and a decrease in apoptotic cells in the hippocampal region of the brain. These observations suggested that osthole promoted NSC proliferation, supported neurogenesis, and thus efficiently rescued impaired neurons in the hippocampus and ameliorated cognitive impairment. We also found that osthole treatment activated the Notch pathway and upregulated the expression of self-renewal genes Notch 1 and Hes 1 mRNA in NSCs. However, when Notch activity was blocked by the γ-secretase inhibitor DAPT, the augmentation of Notch 1 and Hes 1 protein was ameliorated, and the proliferation-inducing effect of osthole was abolished, suggesting that the effects of osthole are at least in part mediated by activation of the Notch pathway.

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Progesterone attenuates Aβ 25–35 -induced neuronal toxicity via JNK inactivation and progesterone receptor membrane component 1-dependent inhibition of mitochondrial apoptotic pathway

Cited by 53 publications

References 52 publications

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice

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