en
Scientific article
Open access
English

A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies

Published inBrain, vol. 139, no. Pt 5, p. 1587-1604
Publication date2016-05
First online date2016-03-08
Abstract

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

eng
Keywords
  • Alzheimer's disease
  • Antibody
  • Cellular implant
  • Encapsulation
  • Immunization
  • Alzheimer Disease / prevention & control
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / immunology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / blood
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / pharmacology
  • Brain / metabolism
  • Cells, Cultured
  • Drug Implants
  • Immunization, Passive / methods
  • Mice
  • Mice, Transgenic
  • Neuroprotection
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / pharmacology
  • Subcutaneous Absorption
  • Tauopathies / prevention & control
Affiliation Not a UNIGE publication
Citation (ISO format)
LATHUILIERE, Aurélien et al. A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies. In: Brain, 2016, vol. 139, n° Pt 5, p. 1587–1604. doi: 10.1093/brain/aww036
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal0006-8950
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