Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1.
Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP/PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated beta-amyloid, and characterized as CD11b(+)/CD11c(-)/MHC class II(-)/TNF-alpha(+) cells, impeded neurogenesis from adult neural stem/progenitor cells, whereas CD11b(+)/CD11c(+)/MHC class II(+)/TNF-alpha(-) microglia, a phenotype induced by IL-4, counteracted the adverse beta-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.
Butovsky
Oleg
O
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Koronyo-Hamaoui
Maya
M
Kunis
Gilad
G
Ophir
Eran
E
Landa
Gennady
G
Cohen
Hagit
H
Schwartz
Michal
M
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D005802:Genes, MHC Class II; D000068717:Glatiramer Acetate; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D018782:Maze Learning; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000502:physiology; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; D039521:CD11c Antigen; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D010455:Peptides; D053764:Presenilin-1; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D000068717:Glatiramer Acetate; D007334:Insulin-Like Growth Factor I