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Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

ABSTRACT: Accumulation of amyloid beta-peptide (A?) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). A? vaccination removes A? deposits from the brain. A? immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal A? deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and A? fragments produced by catalytic antibodies are less likely to form aggregates, A?-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-A? antibodies. Additionally, catalytic antibodies may remove A? more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of A? molecules. We previously isolated A?-specific catalytic antibody, IgVL5D3, with strong A?-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced A? 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-A? catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.

SUBMITTER: Kou J

PROVIDER: S-EPMC4198531 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

Kou Jinghong J Yang Junling J Lim Jeong-Eun JE Pattanayak Abhinandan A Song Min M Planque Stephanie S Paul Sudhir S Fukuchi Ken-Ichiro K

Molecular neurobiology 20140415 1

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 likel ...[more]

PMID: 24733587

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Project description:BACKGROUND: Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against ?-amyloid (A?) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain A? deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. METHODS: We first determined the effect of IVIG on A? toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of A? burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed A? deposits from brain sections of APP/PS1 mice or promotes A? removal by primary glial cells. We determined the role of lysosomal degradation pathway and A? Abs in the IVIG-promoted reduction of A?. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human A? in a mouse model of AD in vivo. RESULTS: IVIG was protective against A? toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic A?1-42 but did not solubilize natively formed brain A? deposits ex vivo. IVIG enhanced microglia-mediated A? clearance ex vivo, with a mechanism linked to A? Abs and lysosomal degradation. The IVIG-enhanced A? clearance appears specific for microglia since IVIG did not affect A? clearance by astrocytes. The cellular mechanisms of A? clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the hippocampus and bound selectively to A? deposits in co-localization with microglia. CONCLUSIONS: Our results demonstrate that IVIG promotes recognition and removal of natively formed brain A? deposits by primary microglia involving natural A? Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to A? deposits in brain parenchyma.

Dataset Information

Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

Publications

Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

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