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Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

Publication ,  Journal Article
Zhao, L; Gottesdiener, AJ; Parmar, M; Li, M; Kaminsky, SM; Chiuchiolo, MJ; Sondhi, D; Sullivan, PM; Holtzman, DM; Crystal, RG; Paul, SM
Published in: Neurobiol Aging
August 2016

The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.

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Published In

Neurobiol Aging

DOI

EISSN

1558-1497

Publication Date

August 2016

Volume

44

Start / End Page

159 / 172

Location

United States

Related Subject Headings

  • Risk Factors
  • Neurology & Neurosurgery
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Genotype
  • Genetic Vectors
  • Genetic Therapy
  • Gene Transfer Techniques
  • Disease Models, Animal
  • Dependovirus
 

Citation

APA
Chicago
ICMJE
MLA
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Zhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., … Paul, S. M. (2016). Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging, 44, 159–172. https://doi.org/10.1016/j.neurobiolaging.2016.04.020
Zhao, Lingzhi, Andrew J. Gottesdiener, Mayur Parmar, Mingjie Li, Stephen M. Kaminsky, Maria J. Chiuchiolo, Dolan Sondhi, et al. “Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.Neurobiol Aging 44 (August 2016): 159–72. https://doi.org/10.1016/j.neurobiolaging.2016.04.020.
Zhao L, Gottesdiener AJ, Parmar M, Li M, Kaminsky SM, Chiuchiolo MJ, et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging. 2016 Aug;44:159–72.
Zhao, Lingzhi, et al. “Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.Neurobiol Aging, vol. 44, Aug. 2016, pp. 159–72. Pubmed, doi:10.1016/j.neurobiolaging.2016.04.020.
Zhao L, Gottesdiener AJ, Parmar M, Li M, Kaminsky SM, Chiuchiolo MJ, Sondhi D, Sullivan PM, Holtzman DM, Crystal RG, Paul SM. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging. 2016 Aug;44:159–172.
Journal cover image

Published In

Neurobiol Aging

DOI

EISSN

1558-1497

Publication Date

August 2016

Volume

44

Start / End Page

159 / 172

Location

United States

Related Subject Headings

  • Risk Factors
  • Neurology & Neurosurgery
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Genotype
  • Genetic Vectors
  • Genetic Therapy
  • Gene Transfer Techniques
  • Disease Models, Animal
  • Dependovirus