A novel recombinant adeno-associated virus vaccine reduces behavioral impairment and beta-amyloid plaques in a mouse model of Alzheimer's disease.
Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). Deposition of the amyloid-beta peptide (Abeta) in brain, particularly its 42-amino acid isoform (Abeta42), has been shown to play a primary and crucial role in the pathogenesis of AD. In this study we have developed a recombinant adeno-associated virus (AAV) vaccine against AD. This vaccine could express CB-Abeta42 (cholera toxin B subunit and Abeta42 fusion protein) in vivo. A single administration of the AAV-CB-Abeta42 vaccine induced a prolonged, strong production of Abeta-specific serum IgG in transgenic mice that overexpressed the London mutant of amyloid precursor protein (APP/V717I), and resulted in improved ability of memory and cognition, decreased Abeta deposition in the brain, and a resultant decrease in plaque-associated astrocytosis. Our results extended the immunological approaches for the treatment and prevention of AD to an oral, intranasal, or intramuscular route that might be better tolerated in human patients than repetitive parental immunizations in the presence of adjuvant. AAV has attracted tremendous interest as a promising vector for gene delivery. Our results raised the possibility that AAV-CB-Abeta42 vector immunization may provide the basis of a novel and promising Alzheimer's disease vaccination program.
Zhang
Jianmin
J
Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 100005 Beijing, People's Republic of China.
Wu
Xiaobing
X
Qin
Chuan
C
Qi
Jin
J
Ma
Shibin
S
Zhang
Huiyuan
H
Kong
Qingli
Q
Chen
Dongqing
D
Ba
Denian
D
He
Wei
W
D000256:Adenoviridae / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000276:immunology / Q000494:pharmacology; D006224:Cricetinae; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D005911:Gliosis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D014614:Vaccines, Synthetic / Q000276:immunology / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C075222:amyloid beta-protein (1-42); D002772:Cholera Toxin