Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease

Jean Cosme Dodart, Robert A. Marr, Milla Koistinaho, Beth M. Gregersen, Seema Malkani, Inder M. Verma, Steven M. Paul

Research output: Contribution to journalArticlepeer-review

166 Scopus citations

Abstract

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the ε4 allele increasing and the ε2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-β peptide (Aβ) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Aβ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Aβ1-42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Aβ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Aβ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Aβ burden and the subsequent development of neuritic plaques.

Original languageEnglish
Pages (from-to)1211-1216
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number4
DOIs
StatePublished - Jan 25 2005

Keywords

  • Amyloid plaques
  • Gene therapy

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