Targeting Alzheimer's disease genes with RNA interference: an efficient strategy for silencing mutant alleles

Nucleic Acids Res. 2004 Jan 30;32(2):661-8. doi: 10.1093/nar/gkh208. Print 2004.


Tau and amyloid precursor protein (APP) are key proteins in the pathogenesis of sporadic and inherited Alzheimer's disease. Thus, developing ways to inhibit production of these proteins is of great research and therapeutic interest. The selective silencing of mutant alleles, moreover, represents an attractive strategy for treating inherited dementias and other dominantly inherited disorders. Here, using tau and APP as model targets, we describe an efficient method for producing small interfering RNA (siRNA) against essentially any targeted region of a gene. We then use this approach to develop siRNAs that display optimal allele-specific silencing against a well-characterized tau mutation (V337M) and the most widely studied APP mutation (APPsw). The allele-specific RNA duplexes identified by this method then served as templates for constructing short hairpin RNA (shRNA) plasmids that successfully silenced mutant tau or APP alleles. These plasmids should prove useful in experimental and therapeutic studies of Alzheimer's disease. Our results suggest guiding principles for the production of allele-specific siRNA, and the general method described here should facilitate the production of gene-specific siRNAs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Alzheimer Disease / genetics*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Base Sequence
  • COS Cells
  • DNA-Directed RNA Polymerases / metabolism
  • Genes, Reporter / genetics
  • HeLa Cells
  • Humans
  • Mutation / genetics*
  • RNA Interference*
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / metabolism*
  • Substrate Specificity
  • Viral Proteins
  • tau Proteins / genetics


  • Amyloid beta-Protein Precursor
  • RNA, Small Interfering
  • Viral Proteins
  • tau Proteins
  • bacteriophage T7 RNA polymerase
  • DNA-Directed RNA Polymerases