Peripheral administration of antisense oligonucleotides targeting the amyloid-β protein precursor reverses AβPP and LRP-1 overexpression in the aged SAMP8 mouse brain

J Alzheimers Dis. 2012;28(4):951-60. doi: 10.3233/JAD-2011-111517.

Abstract

The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 μg of AβPP or control antisense 3 times over 2 week intervals to 12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ(40). Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ(40) increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse.

Publication types

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

MeSH terms

  • Aging / metabolism*
  • Aging / pathology
  • Amyloid beta-Protein Precursor / antagonists & inhibitors
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Drug Delivery Systems
  • Gene Expression Regulation*
  • Male
  • Mice
  • Mice, Transgenic
  • Oligonucleotides, Antisense / administration & dosage*
  • Receptors, LDL / antagonists & inhibitors
  • Receptors, LDL / metabolism*
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Lrp1 protein, mouse
  • Oligonucleotides, Antisense
  • Receptors, LDL
  • Tumor Suppressor Proteins