Dose and Promoter Effects of Adeno-Associated Viral Vector for Green Fluorescent Protein Expression in the Rat Brain

Klein, Ronald L.; Hamby, Mary E.; Gong, Yan; Hirko, Aaron C.; Wang, Samuel; Hughes, Jeffrey A.; King, Michael A.; Meyer, Edwin M.

doi:10.1006/exnr.2002.7942

Cited by 145 publications

(102 citation statements)

References 27 publications

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“…In this respect, the choice of vector is critical. In agreement with other reports, [31][32][33][34] we have shown that an AAV2-based vector can maintain expression of the transgene and hence of the therapeutic protein for 41 year. In addition to the choice of vector, the choice of promoter is also critical for long-term high …”

Section: Durationsupporting

confidence: 93%

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

et al. 2005

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Section: Durationsupporting

confidence: 93%

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

et al. 2005

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“…Kugler and colleagues have shown that gene expression from AAV2 or AAV5 can be restricted to neurons in vitro by incorporating the hSYN or CBA promoter or restricted mainly to astrocytes by using the mCMV promoter [18,20,27]. The hSYN promoter also confers neuronal specificity in vivo [20,27].…”

Section: Discussionmentioning

confidence: 99%

“…The hSYN promoter also confers neuronal specificity in vivo [20,27]. Klein, Meyer and colleagues have demonstrated transduction of cultures of astrocytes, microglia and cortical neurons using AAV2 or AAV8 with the CBA promoter [12,17,18]. In a quantitative comparison of 10 promoters in AAV2 vectors, in cultures of rat hippocampal, cortical, striatal and nigral cells, the 1.8kb NSE promoter and the 2.5kb EF1α promoter mediated the strongest expression; unfortunately, these were two of the largest promoters tested [35].…”

Section: Discussionmentioning

confidence: 99%

Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity

Royo¹,

Vandenberghe²,

Ma³

et al. 2008

Brain Research

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Most current methods of gene delivery for primary cultured hippocampal neurons are limited by toxicity, transient expression, the use of immature neurons, and/or low efficiency. We performed a direct comparison of seven serotypes of adeno-associated virus (AAV) vectors for genetic manipulation of primary cultured neurons in vitro. Serotypes 1, 2, 7, 8 and 9 mediated highly efficient, nontoxic, stable long-term gene expression in cultured cortical and hippocampal neurons aged 0-4 weeks in vitro; serotypes 5 and 6 were associated with toxicity at high doses. AAV1 transduced over 90% of all cells with approximately 80% of the transduced cells being neurons. The method was readily adapted to a high-throughput format to demonstrate neurotrophin-mediated neuroprotection from glutamate toxicity in cultured neurons at 2 weeks in vitro. These vectors should prove highly useful for efficient overexpression or downregulation of genes in primary neuronal cultures at any developmental stage.

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“…The promoter/enhancer combination used to drive expression included the hybrid cytomegalovirus/chicken β-actin promoter (Niwa et al, 1991) and the 3′ enhancer woodchuck hepatitis virus post-transcriptional regulatory element (WPRE, Loeb et al, 1999) as described previously (Klein et al, 2002b). Plasmids for the reporter control green fluorescent protein (GFP) and the P301L form of human tau including exons 2, 3, and 10 (four repeat microtubule-binding domains, 4R2N) were described previously (Klein et al, 2002b(Klein et al, , 2004.Plasmids for human WT tau (4R2N), human ASN with A30P or A53T, and human glial cell line-derived neurotrophic factor (GDNF) were also constructed with the AAV-2 cytomegalovirus/chicken β-actin promoter-WPRE expression cassette. We previously showed that WPRE enhanced expression of GFP, nerve growth factor, or tau (Klein et al, 2002b(Klein et al, ,c, 2004; the same was true for ASN.…”

mentioning

confidence: 99%

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

Klein

Dayton

Lin

et al. 2005

Neurobiology of Disease

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Using a viral vector for mutant (P301L) tau, we studied the effects of gene transfer to the rat substantia nigra in terms of structural and functional properties of dopaminergic neurons. The mutant tau vector caused progressive loss of pars compacta dopaminergic neurons over time, reduced striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. In addition, structural studies demonstrated neurofibrillary tangles and neuritic pathology. Wild-type tau had similar effects on neuronal loss and rotational behavior. In contrast, mutant α-synuclein vectors did not induce rotational behavior, although α-synuclein filaments formed in nigrostriatal axons. Dopamine neuron function is affected by tau gene transfer and appears to be more susceptible to tau-rather than α-synuclein-related damage in this model. Both tau and α-synuclein are important for substantia nigra neurodegeneration models in rats, further indicating their potential as therapeutic targets for human diseases involving loss of dopamine neurons. KeywordsAdeno-associated virus; α-Synuclein; Neurodegeneration; Neurofibrillary tangles; Substantia nigra; Tau Deposits of the microtubule-associated protein tau in the form of neurofibrillary tangles (NFTs) are characteristic of many neurodegenerative diseases including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with parkinsonism linked to chromosome 17 , and in all of these diseases, NFTs are expressed in the substantia nigra (SN; Mirra et al., 1999;Poorkaj et al., 2002;Schneider et al., 2002;Wakabayashi et al., 1994). There is dramatic loss of pigmented SN neurons in PSP and FTDP-17 (Mirra et al., 1999) which may be causally related to toxic aggregation of tau. This study investigates the causal relationship of tau expression and SN dopamine neuron degeneration in an animal model. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMutation in the tau gene causes FTDP-17 (Hutton et al., 1998), and particular variants are associated with increased risk for other parkinsonian disorders, including PSP (Baker et al., 1999) and CBD (Di Maria et al., 2000). Variants may also be a risk factor for Parkinson's disease (PD;Healy et al., 2004;Martin et al., 2001). The P301L FTDP-17-related form of tau is particularly pathogenic as it exhibits accelerated filament formation in vitro (Nacharaju et al., 1999) and transgenic mice expressing P301L tau develop neurofibrillary tangles (NFTs; Lewis et al., 2000). While idiopathic PD is not associated with NFTs, tau has been demonstrated in a subpopulation of Lewy bodies (Ishizawa et al., 2003). Using a viral vector for P301L tau, we previously developed a rat model for NFT formation in the basal forebrain (Klein et al., 2004). Here we targeted wild type or P301L tau expression to the rat SN in order to study the causal relationship between neurofibrillary pathology and loss of dopamine neurons, as a number of tau...

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Dose and Promoter Effects of Adeno-Associated Viral Vector for Green Fluorescent Protein Expression in the Rat Brain

Cited by 145 publications

References 27 publications

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

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