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

Lingzhi Zhao, Andrew J. Gottesdiener, Mayur Parmar, Mingjie Li, Stephen M. Kaminsky, Maria J. Chiuchiolo, Dolan Sondhi, Patrick M. Sullivan, David M. Holtzman, Ronald Crystal, Steven M. Paul

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)159-172
Number of pages14
JournalNeurobiology of Aging
Volume44
DOIs
Publication statusPublished - 1 Aug 2016
Externally publishedYes

Fingerprint

Apolipoprotein E2
Dependovirus
Amyloid
Alzheimer Disease
Pathology
Brain
Genes
Alleles
Apolipoproteins E
Age of Onset
Apolipoprotein E4
Amyloidosis
Genotype
Peptides
Injections

Keywords

  • Adeno-associated virus
  • Alzheimer's disease
  • Amyloid pathology
  • Apolipoprotein E2
  • Gene delivery

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. / Zhao, Lingzhi; Gottesdiener, Andrew J.; Parmar, Mayur; Li, Mingjie; Kaminsky, Stephen M.; Chiuchiolo, Maria J.; Sondhi, Dolan; Sullivan, Patrick M.; Holtzman, David M.; Crystal, Ronald; Paul, Steven M.

In: Neurobiology of Aging, Vol. 44, 01.08.2016, p. 159-172.

Research output: Contribution to journalArticle

Zhao, L, Gottesdiener, AJ, Parmar, M, Li, M, Kaminsky, SM, Chiuchiolo, MJ, Sondhi, D, Sullivan, PM, Holtzman, DM, Crystal, R & Paul, SM 2016, 'Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models', Neurobiology of Aging, vol. 44, pp. 159-172. https://doi.org/10.1016/j.neurobiolaging.2016.04.020
Zhao, Lingzhi ; Gottesdiener, Andrew J. ; Parmar, Mayur ; Li, Mingjie ; Kaminsky, Stephen M. ; Chiuchiolo, Maria J. ; Sondhi, Dolan ; Sullivan, Patrick M. ; Holtzman, David M. ; Crystal, Ronald ; Paul, Steven M. / Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. In: Neurobiology of Aging. 2016 ; Vol. 44. pp. 159-172.
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