NDLI: Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer’s Disease: Prophylactic and Therapeutic Applications

Content Provider	Springer Nature Link
Author	Kou, Jinghong Yang, Junling Lim, Jeong Eun Pattanayak, Abhinandan Song, Min Planque, Stephanie Paul, Sudhir Fukuchi, Ken ichiro
Copyright Year	2014
Abstract	Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer’s disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgV$_{L}$5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgV$_{L}$5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgV$_{L}$5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgV$_{L}$5D3 in the unilateral hemisphere. IgV$_{L}$5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgV$_{L}$5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgV$_{L}$5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.
Starting Page	43
Ending Page	56
Page Count	14
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	51
Issue Number	1
e-ISSN	15591182
Language	English
Publisher	Springer US
Publisher Date	2014-04-15
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Alzheimer’s disease Amyloid Inflammation Antibody Adeno-associated virus Immunotherapy Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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