Peripheral delivery of a CNS targeted, metalo-protease reduces aβ toxicity in a mouse model of Alzheimer's disease

PLoS One. 2011 Jan 31;6(1):e16575. doi: 10.1371/journal.pone.0016575.

Abstract

Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, is the most common form of dementia. Therapeutic options have been elusive due to the inability to deliver proteins across the blood-brain barrier (BBB). In order to improve the therapeutic potential for AD, we utilized a promising new approach for delivery of proteins across the BBB. We generated a lentivirus vector expressing the amyloid β-degrading enzyme, neprilysin, fused to the ApoB transport domain and delivered this by intra-peritoneal injection to amyloid protein precursor (APP) transgenic model of AD. Treated mice had reduced levels of Aβ, reduced plaques and increased synaptic density in the CNS. Furthermore, mice treated with the neprilysin targeting the CNS had a reversal of memory deficits. Thus, the addition of the ApoB transport domain to the secreted neprilysin generated a non-invasive therapeutic approach that may be a potential treatment in patients with AD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / drug effects*
  • Animals
  • Apolipoproteins B / administration & dosage
  • Apolipoproteins B / genetics
  • Apolipoproteins B / therapeutic use
  • Blood-Brain Barrier / metabolism
  • Central Nervous System / metabolism*
  • Drug Delivery Systems / methods*
  • Genetic Vectors / administration & dosage
  • Humans
  • Memory Disorders / drug therapy
  • Metalloproteases / administration & dosage
  • Metalloproteases / therapeutic use
  • Mice
  • Mice, Transgenic
  • Neprilysin / administration & dosage*
  • Neprilysin / genetics
  • Neprilysin / therapeutic use
  • Recombinant Fusion Proteins / administration & dosage

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins B
  • Recombinant Fusion Proteins
  • Metalloproteases
  • Neprilysin