Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease

McGinley, Lisa M.; Sims, Erika J.; Lunn, J. Simon; Kashlan, Osama N.; Chen, Kevin S.; Bruno, Elizabeth; Pacut, Crystal; Hazel, Tom; Johe, Karl; Sakowski, Stacey A.; Feldman, Eva L.

doi:10.5966/sctm.2015-0103

Cited by 69 publications

(73 citation statements)

References 92 publications

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“…30 In a more recent study, a human cortex-derived neural stem cell line modified to express IGF-1 was shown to exhibit neuroprotective capacity in vitro and persists in targeted brain regions in an animal model of AD. 54 In studying the molecular mechanism of IGF-1, we have found that IGF-1 increased the SUMOylation of HDAC1 in rat hippocampus. This result suggests that HDAC1 SUMOylation is a novel mechanism underlying the neuroprotective action of IGF-1.…”

Section: Discussionmentioning

confidence: 96%

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Tao

Hsu

et al. 2017

Cell Death Differ

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Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD. Cell Death and Differentiation (2017) 24, 597-614; doi:10.1038/cdd.2016.161; published online 10 February 2017The brain of Alzheimer's disease (AD) patient is characterized by the accumulation of senile plaques, and amyloid-β peptides (Aβ 1-40 and Aβ 1-42 ) are the major components of these senile plaques. Aβ is known to cause lipid peroxidation, free radical production, caspase 3 activation and DNA damage that eventually lead to neuronal death. [1][2][3] In addition, the Aβ peptide or overexpression of Aβ causes cognitive impairment in animals. 4,5 This cognitive impairment correlates with amyloid plaque formation 4,6 or precedes it. 7,8 Further, naturally secreted Aβ or the Aβ peptide also inhibits longterm potentiation (LTP) in the hippocampus in vivo and disrupts synaptic and network function. 9,10 More recently, we have found that Aβ induces the expression of activated signal transducer and activator of transcription-1 (STAT1) and Aβ induction of STAT1 mediates the memory-impairing effect of Aβ. 11 On the other hand, it is conceivable that when Aβ produces its toxicity, neurons would develop defense mechanisms to cope with Aβ toxicity. For example, a nonamyloidogenic neurotrophic peptide sAPPα is shown to activate neuroprotectin D1 and promote cell survival. 12 In addition, we have found that Aβ activates the MAPK/ERK-SGK (serum-and glucocorticoid-inducible kinase) signaling pathway for neuroprotection against Aβ insult. 13 However, with the role and mechanism of Aβ-induced toxicity been studied extensively, the endogenous protection mechanism induced by Aβ is less well known.Histone acetylation is one kind of epigenetic regulations that has an important role in a wide range of brain functions and disorders, and histone deacetylases (HDACs) regulate the homeostasis of histone acetylation. The HDAC family contains 18 HDAC proteins that belong to different classifications. Inhibitio...

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Section: Discussionmentioning

confidence: 96%

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Tao

Hsu

et al. 2017

Cell Death Differ

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“…Male Tg‐AD B6C3‐Tg(APPswe/PSEN1ΔE9)85Dbo/J (APP/PS1) mice were obtained from the Jackson Laboratory (Bar Harbor, ME). Research grade human NSCs, NSI‐HK532‐IGF‐I, a modified line we previously characterized,15 were provided by Neuralstem, Inc. (Germantown, MD). NSCs were administered to 12‐week‐old mice by three injections into the CC bilaterally at three sites (total six injections), represented by the following atlas coordinates from the bregma (posterior, lateral, ventral): −0.82/(±)0.6/1.9, −1.82/(±)0.6/1.5, −2.3/(±)0.6/1.5 mm, respectively.…”

Section: Methodsmentioning

confidence: 99%

Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice

McGinley

Kashlan

Chen

et al. 2017

Ann Clin Transl Neurol

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The hippocampus has been the target of stem cell transplantations in preclinical studies focused on Alzheimer's disease, with results showing improvements in histological and behavioral outcomes. The corpus callosum is another structure that is affected early in Alzheimer's disease. Therefore, we hypothesize that this structure is a novel target for human neural stem cell transplantation in transgenic Alzheimer's disease mouse models. This study demonstrates the feasibility of targeting the corpus callosum and identifies an effective immunosuppression regimen for transplanted neural stem cell survival. These results support further preclinical development of the corpus callosum as a therapeutic target in Alzheimer's disease.

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“…IGF-I expression has been found in neural stem cells derived from fetal human forebrains [57], and most likely it is induced by GH in the human adult brain [58]. The IGF-I receptor (IGF-IR) maintains a stable expression in the brain throughout life, at least in rats [59], but it is likely that it also occurs in human adults to bind to free IGF-I, which reaches the brain from plasma [60].…”

Section: Discussionmentioning

confidence: 99%

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

Devesa¹,

Devesa²,

Carrillo³

et al. 2018

Reports

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Abstract:(1) This study describes the good evolution of a 6-year-old girl genetically diagnosed (R106X) with Rett syndrome (RTT), after having been treated with IGF-I, melatonin (MT), blackcurrant extracts (BC) and rehabilitated for 6 months. (2) The patient stopped normal development in the first year of age. The patient showed short stature and weight and fulfilled the main criteria for typical RTT. Despite her young age, there was pubic hair (Tanner II), very high plasma testosterone, and low levels of plasma gonadotrophins. There were no adrenal enzymatic deficits, and abdominal ultrasound studies were normal. The treatment consisted of IGF-I (0.04 mg/kg/day, 5 days/week, subcutaneous (sc)) for 3 months and then 15 days of rest, MT (50 mg/day, orally, without interruption) and neurorehabilitation. A new blood test, after 3 months of treatment, was absolutely normal and the pubic hair disappeared (Tanner I). Then, a new treatment was started with IGF-I, MT, and BC for another 3 months. In this period, the degree of pubertal development increased to Tanner III (pubic level), without a known cause. (3) The treatment followed led to clear improvements in most of the initial abnormalities, perhaps due to the neurotrophic effect of IGF-I, the antioxidant effects of MT and BC, and the cerebral increase in the cyclic glycine-proline (cGP) achieved with administration of BC. (4) A continuous treatment with IGF-I, MT, and BC appears to be useful in RTT.

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Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease

Cited by 69 publications

References 92 publications

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

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