Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

Hong, Chang‐Sook; Goins, William F.; Goss, James R.; Burton, Edward A.; Glorioso, Joseph C.

doi:10.1038/sj.gt.3302719

Cited by 96 publications

(64 citation statements)

References 50 publications

(54 reference statements)

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“…Experimental depletion of endogenous NEP activity by pharmacological inhibitors (Iwata et al 2000;Hauss-Wegrzyniak and Wenk 2002;Newell et al 2003;Mouri et al 2006) or reduction of NEP expression by molecular approaches (Madani et al 2006;Farris et al 2007) results in neural accumulation of Ab. Conversely, experimental manipulations that increase brain expression of NEP also increase Ab catabolism and reduce Ab burden (Leissring et al 2003;Marr et al 2003;Hong (Ramsden et al 2003;Rosario et al 2006). Despite the significant role of NEP in reducing Ab levels in brain, little is known about factors that regulate its neural expression.…”

Section: Discussionmentioning

confidence: 99%

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Yao

Nguyen

Rosario

et al. 2008

Journal of Neurochemistry

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Age‐related testosterone depletion in men is a risk factor for Alzheimer’s disease. Prior studies suggest that androgens affect Alzheimer’s disease risk by regulating accumulation of β‐amyloid protein (Aβ) by an undefined mechanism. In this study, we investigated the role of the Aβ‐catabolizing enzyme neprilysin (NEP) in this process. First, we observed that androgens positively regulate neural expression of NEP in adult male rats. Next, we investigated androgen regulatory effects on both NEP expression and Aβ levels using cultured hippocampal neurons and neuronally differentiated rat pheochromocytoma cell 12 with or without androgen receptor (AR). Dihydrotestosterone (DHT) induced a time‐dependent increase in NEP expression. DHT also significantly decreased levels of Aβ in AR‐expressing cells transfected with amyloid precursor protein, but did not affect levels of either full‐length or non‐amyloidogenic, soluble amyloid precursor protein. Importantly, the DHT induced decrease of Aβ was blocked by pharmacological inhibition of NEP. The DHT‐mediated increase in NEP expression and decrease in Aβ levels were (i) not observed in rat pheochromocytoma cell 12 lacking AR and (ii) blocked in AR‐expressing cells by the antagonists, cyproterone acetate and flutamide. Together, these findings suggest that androgen regulation of Aβ involves an AR‐dependent mechanism requiring up‐regulation of the Aβ catabolizing enzyme NEP.

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Section: Discussionmentioning

confidence: 99%

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Yao

Nguyen

Rosario

et al. 2008

Journal of Neurochemistry

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“…17,21,[144][145][146][147] Non-replicative HSV vectors have been tested in many different gene therapy animal models of various neuropathies, Parkinson's disease, [148][149][150] Alzheimer's disease, 151 chronic pain 152,153 or lysosomal storage disorders with neurological involvement. 154 Therapy of lysosomal storage disorders with neurological involvement such as Tay-Sachs (TS) disease requires production and distribution of the missing enzyme into the CNS.…”

Section: Replication-defective Vectorsmentioning

confidence: 99%

HSV as a vector in vaccine development and gene therapy

Marconi

Argnani

Epstein³

et al. 2008

Human Vaccines

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“…The serine that regulates 14-3-3 binding to TH is phospho-Ser19 (PSer19), a site that is highly phosphorylated in dopaminergic neurons throughout the brain [36]. To evaluate the impact of α-Syn on TH in vivo, in the absence of endogenous α-Syn, we obtained ASKO mice [1] and generated wild type human α-Syn lentivirus using established methodologies [16]. Herein, we share our novel findings revealing that when α-Syn becomes aggregated, immunoreactivity (ir) for Total-TH appears to be reduced in dopaminergic neurons.…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice

Alerte

Akinfolarin

Friedrich

et al. 2008

Neuroscience Letters

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Tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis, is frequently used as a marker of dopaminergic neuronal loss in animal models of Parkinson's disease (PD). We have been exploring the normal function of the PD-related protein α-synuclein (α-Syn) with regard to dopamine synthesis. TH is activated by the phosphorylation of key seryl residues in the THregulatory-domain. Using in vitro models, our laboratory discovered that α-Syn inhibits TH by acting to reduce TH phosphorylation, which then reduces dopamine synthesis [31,33]. We recently began exploring the impact of α-Syn on TH in vivo, by transducing dopaminergic neurons in α-Syn knockout mouse (ASKO) olfactory bulb using wild type human α-Syn lentivirus. At 3.5 -21 days after viral delivery, α-Syn expression was transduced in periglomerular dopaminergic neurons. Cells with modest levels of α-Syn consistently co-labeled for Total-TH. However, cells bearing aggregated α-Syn, as revealed by proteinase K or Thioflavin-S treatment had significantly reduced Total-TH immunoreactivity, but high phosphoserine-TH labeling. On immunoblots, we noted that Total-TH immunoreactivity was equivalent in all conditions, although tissues with α-Syn aggregates again had higher phosphoserine-TH levels. This suggests that aggregated α-Syn is no longer able to inhibit TH. Although the reason(s) underlying reduced Total-TH immunoreactivity on tissue sections await(s) confirmation, the dopaminergic phenotype was easily verified using phosphorylation-state-specific TH antibodies. These findings have implications not only for normal α-Syn function in TH regulation, but also for measuring cell loss that is associated with synucleinopathy. KeywordsParkinson's disease; lentivirus; knockout mice; transduction Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Short term regulation of TH depends on the phosphorylation of seryl residues, Ser19, Ser31, and Ser40, in the TH regulatory domain [5,14]. We previously demonstrated significant reduction in TH phosphorylation in dopaminergic cells that overexpress α-Syn [31,33]. The serine that regulates 14-3-3 binding to TH is phospho-Ser19 (PSer19), a site that is highly phosphorylated in dopaminergic neurons throughout the brain [36]. To evaluate the impact of α-Syn on TH in vivo, in the absence of endogenous α-Syn, we obtained ASKO mice [1] and generated wild type human α-Syn lentivirus using established methodologies [16]. Herein, we share our novel findings revealing that when α-Syn becomes aggregated, immunoreactivity (ir) for Total-TH appears to be reduced in dopaminergic...

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Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

Cited by 96 publications

References 50 publications

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

HSV as a vector in vaccine development and gene therapy

α-Synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice

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