Intracranial Injection of AAV Expressing NEP but Not IDE Reduces Amyloid Pathology in APP+PS1 Transgenic Mice

Carty, Nikisha; Nash, Kevin; Brownlow, Milene; Cruite, Dana; Wilcock, Donna M.; Selenica, Maj‐Linda B.; Lee, Daniel; Gordon, Marcia N.; Morgan, Dave

doi:10.1371/journal.pone.0059626

Cited by 38 publications

(29 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tau was cloned into the pTR2-MCS vector with an HA tag appended to the N terminus for detection of the protein expression. Recombinant AAV9 vectors were generated and purified as described previously (Carty et al, 2013). rAAV particle concentrations are expressed as vector genomes/ml (vg/ml).…”

Section: Methodsmentioning

confidence: 99%

“…Vector genomes were quantitated using a modified version of the dot plot protocol described previously . UF11 plasmid was used to generate rAAV9 -green fluorescent protein (GFP) virus as described previously (Carty et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

“…Stereotaxic coordinates from bregma were Ϫ2.7 mm anteroposterior, Ϫ2.7 mm lateral, and Ϫ3.0 mm ventral. The virus was administered using convection-enhanced delivery at a constant rate of 2.5 l/min (Carty et al, 2013). Four months after injection, mice were weighed, anesthetized with barbiturates, and transcardially perfused with 25 ml of 0.9% saline.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

Hunt¹,

Nash

Placides³

et al. 2015

J. Neurosci.

View full text Add to dashboard Cite

Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer's disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete for L-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV-tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

Hunt¹,

Nash

Placides³

et al. 2015

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Expression of neprilysin in the brain via rAAV reduced Aβ load in AD mouse models [26, 56, 57]. IgV L 5D3 exceeds neprilysin in the efficacy (kcat 2.2 vs 6.3/min) and specificity [22, 58].…”

Section: Discussionmentioning

confidence: 99%

Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer’s Disease: Prophylactic and Therapeutic Applications

et al. 2014

View full text Add to dashboard Cite

Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased pro-inflammatory cytokines or infiltrating T cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.

show abstract

“…Carty et al . used intracranial injections to successfully deliver viral vectors expressing therapeutic genes into the frontal cortex of transgenic model of Alzheimer's disease 7 . Thaci et al .…”

Section: Introductionmentioning

confidence: 99%

Creating Anatomically Accurate and Reproducible Intracranial Xenografts of Human Brain Tumors

Pierce

Keating

2014

JoVE

View full text Add to dashboard Cite

Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live animal – particularly in sites with unique physiological and architectural qualities such as the brain. In vitro and ectopic models cannot account for features such as vasculature, blood brain barrier, metabolism, drug delivery and toxicity, and a host of other relevant factors. Orthotopic models have their limitations too, but with proper technique tumor cells of interest can be accurately engrafted into tissue that most closely mimics conditions in the human brain. By employing methods that deliver precisely measured volumes to accurately defined locations at a consistent rate and pressure, mouse models of human brain tumors with predictable growth rates can be reproducibly created and are suitable for reliable analysis of various interventions. The protocol described here focuses on the technical details of designing and preparing for an intracranial injection, performing the surgery, and ensuring successful and reproducible tumor growth and provides starting points for a variety of conditions that can be customized for a range of different brain tumor models.

show abstract

Intracranial Injection of AAV Expressing NEP but Not IDE Reduces Amyloid Pathology in APP+PS1 Transgenic Mice

Cited by 38 publications

References 33 publications

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer’s Disease: Prophylactic and Therapeutic Applications

Creating Anatomically Accurate and Reproducible Intracranial Xenografts of Human Brain Tumors

Contact Info

Product

Resources

About