title: Peripheral delivery of a CNS targeted, metalo-protease reduces aβ toxicity in a mouse model of Alzheimer's disease.
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.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Marr
authors.forename: Ryan
authors.initials: R
authors.lastname: Gindi
authors.forename: Rewati
authors.initials: R
authors.lastname: Potkar
authors.forename: Sarah
authors.initials: S
authors.lastname: Michael
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D000818:Animals; D001055:Apolipoproteins B / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy; D045726:Metalloproteases / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage
chemical_list: D016229:Amyloid beta-Peptides; D001055:Apolipoproteins B; D011993:Recombinant Fusion Proteins; D045726:Metalloproteases; D015260:Neprilysin