Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Abeta1-6 upregulates IL-10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease.
BACKGROUND
One of the pathological hallmarks of Alzheimer's disease (AD) is deposits of amyloid beta-peptide (Abeta) in neuritic plaques and cerebral vessels. Immunization of AD mouse models with Abeta reduces Abeta deposits and improves memory and learning deficits. Because recent clinical trials of immunization with Abeta were halted due to brain inflammation that was presumably induced by a T-cell-mediated autoimmune response, vaccination modalities that elicit predominantly humoral immune responses are currently being developed.


METHODS
We have nasally immunized a young AD mouse model with an adenovirus vector encoding 11 tandem repeats of Abeta1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A (PEDI), AdPEDI-(Abeta1-6)(11), in order to evaluate the efficacy of the vector in preventing Abeta deposits in the brain. We also have investigated immune responses of mice to AdPEDI-(Abeta1-6)(11).


RESULTS
Nasal immunization of an AD mouse model with AdPEDI-(Abeta1-6)(11) elicited a predominant IgG1 response and reduced Abeta load in the brain. The plasma IL-10 level in the AD mouse model was upregulated after immunization and, upon the stimulation with PEDI-(Abeta1-6)(11), marked IL-10 responses were found in splenic CD4(+) T cells from C57BL/6 mice that had been immunized with AdPEDI-(Abeta1-6)(11).


CONCLUSIONS
These results suggest that the induction of Th2-biased responses with AdPEDI-(Abeta1-6)(11) in mice is mediated in part through the upregulation of IL-10, which inhibits activation of dendritic cells that dictate the induction of Th1 cells.
Kim
Hong-Duck
HD
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, PO Box 1649, Peoria, IL 61656, USA.
Tahara
Kazuki
K
Maxwell
J Adam
JA
Lalonde
Robert
R
Fukuiwa
Tatsuya
T
Fujihashi
Kohtaro
K
Van Kampen
Kent R
KR
Kong
Fan-Kun
FK
Tang
De-chu C
DC
Fukuchi
Ken-ichiro
K
D000256:Adenoviridae / Q000235:genetics*; D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D023582:Alzheimer Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics* / Q000276:immunology; D020080:Tandem Repeat Sequences; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
D023582:Alzheimer Vaccines; D000682:Amyloid; D016229:Amyloid beta-Peptides; D007074:Immunoglobulin G; D010446:Peptide Fragments; D019444:Vaccines, DNA; C505239:amyloid beta-protein (1-6); D016753:Interleukin-10